LV13669B - Alpha ketoamide compounds as cysteine protease inhibitors - Google Patents

Abstract

The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.

Description

Alpha ketoamide compounds are tank protease inhibitors

References to Related Applications [0001] This patent application claims a prior art patent application no. 60 / 663,970, filed March 21, 2005; 60 / 684,623, filed May 24, 2005, both patent applications are incorporated herein by reference.

Application for Acquisition of Invention under Federal Supported Research or Development

[0002] NOT APPLICABLE

Reference to " Sequence List ”, Table or Computer Program Attachment Attached to CD

[0003] NOT APPLICABLE

BACKGROUND OF THE INVENTION The present invention relates to compounds which are cysteine protease inhibitors, in particular cathepsins B, K, L, F and S, and therefore are useful in the treatment of diseases in which these proteases are mediators. The subject of this invention is the pharmaceutical compositions containing these compounds and their preparation processes.

Existing state of the art Cysteine proteases are a group of peptidases characterized by the presence of cysteine residues in the catalytic zone of the enzyme. Cysteine proteases are associated with normal protein digestion and processing. But abnormal cysteine protease activity, such as increased appearance or activation, may have pathological effects. In this regard, some cysteine proteases are associated with a number of conditions including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromate leukodistrophy and others. For example, increased levels of cathepsin B · and changes in enzyme degradation have been found in tumors, and this allows the role of the enzyme in tumor invasion and metastasis. In addition, abnormal cathepsin B activity is involved in conditions such as rheumatoid arthritis, osteoarthritis, Pneumocystis carinii, pancreatitis, inflammation of the respiratory tract and bone and joint disorders.

Significant emergence of cathepsin K in osteoclasts and osteoclast-associated nuclei, as well as its high collagenolytic activity, suggests that the enzyme is involved in osteoclast-associated bone resorption and hence bone abnormalities that occur in osteoporosis. In addition, the appearance of cathepsin K in the lungs and its elastinolytic activity suggest that the enzyme also plays a role in lung disorders.

Cathepsin L is involved in normal lysosomal proteolysis, as well as in a number of disease states including, but not limited to, melanoma metastasis. Cathepsin S is involved in Alzheimer's disease and certain autoimmune disorders, including but not limited to adolescent diabetes, the onset of sclerosis, pemphigus vulgaris, Greiva disease, mya thenia ditch, systemic iupus erythematosus, rheumatoid arthritis, neuropathic pain and Hashimoto thyroiditis. Furthermore. Cathepsin S is involved in allergic disorders, including but not limited to asthma; and allogeneic immune responses including, but not limited to, organ transplant or tissue transplant rejection.

[0008] In view of a number of diseases in which the increase in the protease activity of the tank is found to contribute to pathology and / or disease typology, molecules that inhibit the activity of this enzyme group, in particular, molecules that inhibit cathepsin B, K, L, F and \ t / or S may be useful as therapeutic agents.

SUMMARY OF THE INVENTION In a first aspect, the subject of the invention is a compound of formula (I):

¥ H P i I b l

R 1 -N H R 5 h O R 'wherein: R 1 is hydrogen or alkyl; R 2 is cycloalkyl, cycloalkylalkyl, aralkyl, heteroaryl or heteroaralkyl optionally substituted with one or two substituents independently selected from alkyl, alkoxy or halogen; R3 is hydrogen, alkyl or alkoxyalkyl; R4 is alkyl; or R3 and R4 together with the carbon atom to which they are attached form cycloalkylene optionally substituted with one to four fluorine atoms, or heterocycloalkylene optionally substituted with alkyl, alkoxyalkyl, hydroxyalkyl, acyl, cycloalkyl, cycloalkylalkyl or haloalkyl; R5 is alkyl, haloalkyl optionally substituted with cycloalkyl, aryl, heteroaryl or heterocycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, - (alkylene) - X-R9 (wherein X is -O-, -S-, -SO-, -SO 2 -, -CONH-, -NHCO- or -NHSO 2 - and R 9 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroarylgroup, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl) or - (alkylene) -X 1 - (haloalkylene) - R10 (where X1 is -O-, -S-, -SO-, -SO2-, -CONH-, -NHCO- or -NHSO2- and R10 is cycloalkyl, aryl, heteroaryl or heterocycloalkyl) wherein the aromatic or alicyclic ring R5 is optional is substituted by one, two, or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy, cyano, halogen, carboxyl or alkoxycarbonyl; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaryl, aralkyl, heteroaralkyl , cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, acilafkilgrupas, aryloxycarbonyl, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, heterocikloalkiloksikarbonilgrupas, cikloalkiloksikarbonilgrupas, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkiloksigrupas, aminocarbonyl, aminosulfonyl or -SO2R11 (kurR11 alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl); and furthermore, wherein the aromatic or alicyclic ring Rc is optionally substituted with one, two or three Rd independently selected from alkyl, alkylsulfonyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy or halogen; R6 is haloalkyl; R7 is hydrogen, alkyl or haloalkyl; and R8 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl attached via a carbon atom, wherein the aromatic or alicyclic ring R8 is optionally substituted with one, two or three Re independently selected from alkyl, halo, haloalkyl, hydroxyl, alkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, carboxyl, cyano, alkylsulfonyl, alkylsulfonylamino, aminocarbonyl or aminosulfonyl; or a pharmaceutically acceptable salt thereof.

In a second aspect, the subject of the invention is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.

In a third aspect, the subject of the invention is a method for treating an animal in an animal in which the disease involves cysteine proteases, in particular cathepsin S, furthermore, by administering the method, administering to the animal a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a pharmaceutical composition thereof. acceptable salt by mixing with one or more fatty acids.

In a fourth aspect, the subject of the present invention is a process for preparing a compound of formula (I).

In a fifth aspect, the subject of the invention is a method of treatment wherein a patient is subjected to treatment and this treatment induces an immune response in a patient, primarily a harmful immune response, and the patient is administered a compound of formula (I) or a pharmaceutically acceptable salt thereof. Immune response mediators are mainly MHC Group II molecules. The subject matter of this invention 4 may be administered before or after therapy or concurrently therewith. It is better to treat the treatment with a biological treatment. It is better if the therapy contains a small molecule treatment.

It is preferred that the biological preparation is a protein, preferably an antibody, preferably a monoclonal antivief. The best biological agent is Remicade®, Refacto®, Referon-A®, Factor VIII, Factor VII, Betaseron®, Epogen®, Enbrel®, Interferon beta, Botox®, Fabrazyme®, Elspar®, Cerezyme®, Myobloc®, Aldurazyme® , Veduma®, Interferon Aipha, Humira®, Aranesp®, Zevalin® or OKT3.

Preferably, the treatment comprises the use of heparin, low molecular weight heparin, procaineamide or hydralazine.

In a sixth aspect, the subject of the present invention is a method of treating an immune response in an animal when said reaction is caused by administering a biological preparation to an animal using a method, and administering to the animal in need of such treatment an effective compound of formula (I) or a pharmaceutically acceptable salt thereof. quantity.

In a seventh aspect, the subject of the present invention is a method of conducting a clinical trial of a biological preparation administered to a subject participating in a clinical trial to administer a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a biological agent.

In the aspect of the inventor, the subject of the invention is a method of prophylactic treatment when a patient is treated with a biological preparation in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a biological agent-induced immune response in a patient.

In a ninth aspect, the subject of the present invention is a method for detecting a decrease in the efficacy of a biological agent in an animal due to an immune response induced by a biological preparation, wherein the biological preparation is administered to the animal in the presence and absence of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In a tenth aspect, the subject of the invention is a method of improving the efficacy of a biological preparation in an animal, and the biological preparation is administered to the animal in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In the eleventh aspect, the object of the present invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament. It is better for the medicine to treat a disease where the disease mediator is cathepsin S.

In a twelfth aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in combination with a biological preparation in combination therapy wherein the compound of the present invention is treated with a biological preparation. immune response. It is preferred that the compound (s) of the present invention be administered prior to administration of the biological preparation. It is preferable that the compound (s) which are the subject of the present invention be administered with the biological preparation. It is preferred that the compound (s) of the present invention be administered after the administration of the biological preparation.

Detailed description of the invention

Definitions: Unless otherwise stated, the terms used in the description and claims are refined for the purposes of this application and have the following meanings.

"Alicyclic" means a functional group in which carbon atoms are arranged in closed non-aromatic ring structures such as cycloalkyl and heterocycloalkyl as defined herein.

&Quot; Time Group " by itself means a straight or branched, saturated aliphatic residue containing from one to eight carbon atoms unless otherwise indicated, such as alkyl containing methyl, ethynyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, and the like.

&Quot; Alkylene ", unless otherwise indicated, means a straight or branched, saturated aliphatic bivalent residue of one to six carbon atoms, such as methylene (-CH2-), ethylene (-CH2CH2-), trimethylene (-CH2CH2CH2- ), tetramethylene (-CH 2 CH 2 CH 2 CH 2 -) 2-methylethylmethylene (-CH 2 CH (CH 3) CH 2 CH 2 -), pentamethylene (-CH 2 CH 2 GH 2 CH 2 CH 2 -) and the like.

&Quot; Alkylsulfonyl " means a -SO2R residue, wherein R is an alkyl group, as defined herein, such as methylsulfonyl, ethysulfonyl, and the like.

&Quot; Alkylsulfonylamino " means a residue of -NHSO2R wherein R is alkyl as defined herein, such as methylsulfonylamino, ethylsulfonylamino, and the like.

&Quot; alkoxy group " means -OR, where R is alkyl as defined herein, such as methoxy, ethoxy and the like.

&Quot; Alkoxyalkyl " is a linear equal hydrocarbon residue with one to six carbon atoms or a branched, homogenous hydrocarbon residue with three to six carbon atoms substituted by at least one alkoxy group, preferably one or two alkoxy groups as defined above, e.g., 2-methoxyethyl, 1-, 2-or 3-methoxypropyl, 2-ethoxyethyl and the like.

&Quot; Alkoxycarbonyl " means a -C (O) OR residue, R is a predetermined alkyl group such as methoxycarbonyl, ethoxycarbonyl and the like. 6 " Aminoalkyl " is a linear equal hydrocarbon residue of one to six carbon atoms or a branched, homogenous hydrocarbon residue with three to six carbon atoms substituted by at least one, preferably one or two, -NRR 'groups, wherein R is hydrogen, afkyl, acyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or heterocycloalkylalkyl and R 'is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, aminolarbonilgrupa or aminosulfonyl as defined here, for example, aminomethyl, metilamīnoetilgrupa, dimethylaminoethyl, 1,3-diaminopropyl, acetylaminopropyl and the like.

&Quot; Acyl " means a COR residue wherein R is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocycloalkyl as defined herein, e.g. When R is alkyl, it is understood to include alkylcarbonyl in this application.

&Quot; Acylalkyl " is a linear equal hydrocarbon residue of one to six carbon atoms or branched monovalent hydrocarbon with three to six carbon atoms substituted with at least one, preferably one or two, acyl groups as defined herein, e.g. -or-ethyl and the like.

&Quot; Aminocarbonyl " means a -CONRR 'residue wherein R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaryl, or heterocycloalkylalkyl, or R and R 'together with the nitrogen atom to which they are attached form a heterocycloamino group as defined herein.

'Aminosulfonyl' " means a -SO2NRR 'residue wherein R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaryl, or heterocycloalkylalkyl, or R and R 'together with the nitrogen atom to which they are attached form a heterocycloamino group as defined herein.

&Quot; Animal " includes non-human mammals (such as dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, deer and the like) and non-mammals (eg birds and the like).

&Quot; Aromatic " means a functional group whose carbon atoms form an unsaturated ring system and all atoms in the ring system are sp2 hybridized and the total number of pi electrons equals 4n + 2.

&Quot; Aryl " is a monocyclic or fused bicyclic ring system containing 6 to 10 carbon atoms, each ring being aromatic, such as phenyl or naphthyl.

&Quot; Aryloxy " means -O-R, wherein R is aryl as defined above, for example, phenoxy, naphthyloxy, and the like.

&Quot; Aryloxycarbonyl " means a residue of -C (O) OR wherein R is aryl as defined above, for example, phenyloxycarbonyl, naphthyloxycarbonyl and the like.

&Quot; Aralkyl " means a - (alkylene) -R residue, wherein R is aryl as defined above, for example, benzyl, phenethyl and the like.

&Quot; Aralkyloxy " means -OR, wherein R is aralkyl as defined above, for example, benzyloxy, phenethyloxy and the like.

Aralkyloxycarbonyl " means a residue of -C (O) OR wherein R is aralkyl as defined above, for example, benzyloxycarbonyl, phenethyloxycarbonyl and the like.

&Quot; Biological Preparation " means a therapeutic agent obtained from living organisms for the treatment or regulation of the disease. Examples include, but are not limited to, proteins (recombinant and plasma derived), monoclonal or polyclonal, humanized or mouse antibodies, toxins, hormones, and the like. Currently, biotic preparations are used to treat various diseases such as cancer, rheumatoid arthritis and haemophilia.

&Quot; Carboxyl " means a residue of -C (O) OH.

&Quot; Cycloalkyl " means a monovalent saturated monocyclic ring containing three to eight carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, crchexyl and the like.

&Quot; Cycloalkylalkyl " means a - (alkylene) -R residue, wherein R is cycloalkyl as defined above, for example, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl and the like.

&Quot; Cycloalkyloxycarbonyl " means a residue of -C (O) OR wherein R is cycloalkyl as defined above, for example cyclopropyloxycarbonyl, cyclopentyloxycarbonyl and the like.

&Quot; Cycloalkylene " means a bivalent saturated monocyclic ring containing three to eight ring carbon atoms. For example, a case where "R3 and R4, together with the carbon atom to which both R1 and R2 are attached, form a cycloalkylene group", but without being bound by the following:

and the like.

&Quot; Disease " specifically contains any unhealthy condition of an animal or part thereof and contains an unhealthy condition that could be caused or likely to be associated with medical or veterinary therapy applied to this animal, i.e. side effects of this therapy ".

&Quot; Derived " means a similar feature that can be identified.

&Quot; Harmful immune response " means an immune response that inhibits effective patient treatment or causes a disease in a patient. For example, by administering a mouse antibody to a patient for therapeutic or diagnostic purposes, the development of human anti-murine antibodies is delayed or delayed by further treatment. Antibody formation against pure mouse monoclonal antibodies may exceed 70% (see Khazaeli, B. et al. J. lmmwiother. 1994, 15, pp. 42-52; Dillman RO et al. Cancer Biother. 1994, 9, pp. 17- 28; and Reinsberg, J. Hybridoma, 1995, 14, pp. 205-208). Additional examples of known agents that suffer from a harmful immune response are blood coagulation factors such as factor VIII. Factor VIII when administered to patients with haemophilia A restores blood coagulation. Although Factor VIII is a human protein, it does cause an immune response in patients with haemophilia, because they do not have endogenous factor VIII in their blood and thus appear to be a foreign antigen to the immune system. About 29-33% of young patients produce antibodies that bind and neutralize the therapeutically-administered factor VIII (see LusherJ M. Semin Thromb Hemost. 2002, 28 (3), pp.273-276). These neutralizing antibodies require a higher intake of factor VIII to maintain normal blood coagulation parameters, an expensive treatment regimen to induce immune transferability (see BrietEetal. Adv. Exp. Med. Bio. 2001, 489, pp. 89-97). Another immunogenic example is the adenoviral vectors. Reirovirus therapy is still experimental and limited. One reason for this is that the use of therapeutic virus causes an immune response that can block any of the same or similar virus (see Yiping Yang et al. J. ofVirology. 1995, 69, pp. 2004-2015). This ensures that retroviral therapies should be based on the appearance of protein variables or direct inclusion of the viral sequence in the host genome. Targeted studies allowed the identification of several virus-neutralizing epitopes recognized by host antibodies (see Hanne, Gahery-Segard et al. J. of Virology 1998 72, pp. 2388-2397), showing that virus modifications are not sufficient to overcome this obstacle . This invention will allow the process of re-administration of adenoviral therapy to be realized. Another example of an immunogenic product that causes neutralizing antiviral is the well-known Botox. Botulinum toxin protein is purified from Clostridium botulinum fermentation. It is used as a therapeutic agent in muscular disorders such as cervical dystonia, in addition to cosmetic use. Following re-use, patients developed neutralizing antibodies to the toxin, resulting in reduced efficacy (see Blarclein et al. Ann Neurol. 2002, 52, pp. 68-73 and Rollntk, JD et al. Neurol. Clin. Neurophysiol. 2001, 2001 (3) , pp. 2-4). "Harmful immune response" also includes diseases caused by therapeutic agents. A specific example of this is the immune response to the therapy with recombinant human erythropoietin (EPO). Erythroprotein is used to promote red cell growth and to restore red blood cell count in patients after chemotherapy or dialysis. . 9 9 EN 13669

A small percentage of patients develop antibodies to EPO and then these patients do not respond to either the therapeutically-administered EPO or their own endogenous EPO (see Casadevall, N, et al., NEJM. 2002, 346, pp. 469-475). These patients develop a disorder of pure red cell aplasia, in which red blood cell production is rapidly decreasing (see Gershon S.K. et al. NEJM 2002, 346, pp. 1584-1586). This complication of EPO therapy can be fatal if left untreated. Another specific example is the mouse antibody OKT3 (also known as Orthoclone) monoclonal antibody directed to the activated T-cell CD-3 domain. In clinical trials in 20-40% of patients, administration of OKT3 results in anti-therapy antibodies. In addition to neutralizing therapy, these antibodies also stimulate a strong host immune response. The immune response is strong enough to deny entry to patients with high levels of anti-human antibody antibodies (see label on 'Orthoclone' packaging). The last example is the therapeutic agent for human antibodies. Humira® is a monoclonal antibody directed against TNF and used to treat rheumatoid arthritis. Using only this antibody, ~ 12% of patients produce neutralizing antibodies. Additionally, expressed as a percentage of the small number of patients being given the medicine, a systemic lupus erthematosus-like condition develops as a therapeutic-mediated immune response via IgG (see the label on the Humira package).

Another example of a "harmful immune response" is a host response to a small molecule drug. It is known to those skilled in the art that certain chemical structures bind to host proteins by stimulating immune recognition (see Ju.C. etal. 2002 CurrentDrug Metabolism 3, pp. 361-111 and Kimber / et al. 2002, ToxicoIogic Patho! pp. 54-58.) Significant part of these host reactions occurs via IgG. Specific 'harmful immune responses' via IgG are haemolytic anemia, Steven-Johnson syndrome and drug-induced Lupus.

&Quot; Halogen " means fluorine, chlorine, bromine or iodine.

&Quot; Haloaikil " means an alkyl group, as defined above, substituted with one or more, e.g. from one to thirteen, preferably from one to seven halogen atoms, as defined in this application. The haloalkyl group contains monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, and the like, such as chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like.

&Quot; Haloalkylgroup " means an alkylene residue as defined above wherein one of the four, preferably one or two, hydrogen atoms in the alkylene chain is (are) substituted by fluorine (s).

&Quot; Haloalkoxy " means -OR, wherein R is haloalkyl as defined above, for example, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy and the like.

&Quot; Heteroaryl " as a group or part of a group means an aromatic monocyclic or bicyclic functional group having 5 to 10 ring atoms, wherein one or more, preferably one, two or three ring atoms are selected from nitrogen, oxygen or sulfur, and the other ring atoms are carbon. Examples of the Heeroaryl ring include, without limitation, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalineil , pyrazolyl ring and the like.

&Quot; Heteroaryloxy " means -O-R, wherein R is heteroaryl as defined above, for example furanyloxy, pyridinyloxy, indolyloxy, and the like.

&Quot; Heteroaryloxycarbonyl " means a residue of -C (O) 0-R, wherein R is heteroaryl as defined above, for example, pyridinyloxycarbonyl, pyrimidinyloxycarbonyl and the like.

&Quot; Heteroaralkyl " means a - (alkylene) -R residue wherein R is heteroaryl as defined above, for example, pyridinylmethyl, 1- or 2-furanylethyl, imidazolylmethyl and the like.

&Quot; Heroeroid Chemistry " is a -O-R residue wherein R is a heteroaralkyl group as defined above, for example, pyridinylmethyloxy, furanylethyloxy, and the like.

&Quot; Heteroaralkyloxycarbonyl " means a residue of -C (O) 0-R, wherein R is heteroaralkyl as defined above, for example, pyridinylmethyloxycarbonyl, pyrimidinylmethyloxycarbonyl, and the like.

&Quot; Heterocycloalkyl " means a saturated or partially saturated monocyclic or bicyclic residue with 4, 5 or 6 carbon ring atoms, where one or more, preferably one, two or three ring carbon atoms are replaced by a heteroatom selected from -N =, -N-, -O -, -S-, -SO-, or -S (O) 2 -, and further wherein one or two ring carbon atoms are replaced by a keto (- CO -) group. The heterocycloalkyl ring is optionally fused to form a cycloalkyl, aryl or hexeroaryl ring as defined in this application. Typical examples include, without limitation, imidazolidinyl, morpholinyl, thiomorpholinyl, thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxo-tetrahydrothiopyranyl, 1,1-dioxotetratio-pyranyl, indolinyl, indolinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrolinyl, quinuclidinyl, 3,4-dihydroisoquinolinyl, dihydroindolyl, and the like.

If the heterocycloalkyl contains at least one nitrogen atom, this group means a heterocycloamino group and is a heterocycloalkyl group as defined above.

&Quot; Heterocyclylalkylene " is a bivalent heterocyclyl as defined in this application, and an example where "R3 and R4 together with the carbon to which R3 and R4 are attached form a heterocyclylalkylene" " contains, but without limitation, the following: 11

LV 13669 wherein R is a substituent as defined in the Summary of Invention.

&Quot; Heterocycloalkylalkyl " means R, wherein R is heterocycloalkyl as defined above, for example, pyrrolidinylmethyl, tetrahydrofuranylethyl, pyridinylmethylpiperidinylmethyl, and the like.

&Quot; Heterocycloalkyloxycarbonyl " means a residue of -C (O) 0R, wherein R is heterocycloalkyl as defined above, for example, pyridinyloxycarbonyl, pyrimidinyloxycarbonyl and the like.

&Quot; Hydroxy " means -OH residue. Unless otherwise stated, the compounds mentioned in the present invention containing hydroxyl radicals also contain their protected derivatives. Suitable protecting groups for hydroxyl groups are benzyl and the like.

&Quot; Hydroxyalkyl " means a linear equal hydrocarbon residue with one to six carbon atoms or a branched, mono-hydrocarbon residue with three to six carbon atoms substituted with one or two hydroxyl groups, provided that when two hydroxyl groups are present, they are not linked to the same carbon atom; carbon atoms. Typical examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl , 1- (hydroxymethyl) -2-hydroxyethyl, 2,3-dihydro-oxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1- (hydroxymethyl) ) -2-hydroxyethyl.

&Quot; Exorcists " means compounds of formula (I) having the same molecular formula, but which differ in the nature or sequence of attachment of the atoms or in the spatial distribution of their atoms. Isomers that differ in the spatial positioning of the atoms are called "stereoisors." Stereoisomers, which are a mirror image of one another, are called 'diastereoisomers' and stereoisomers that are not superimposed mirror images are called 'enantiomers' or sometimes 'optical isomers'. A carbon atom linked to four non-identical substituents is called a "chiral center". Compounds with one chiral center having two enantiomeric forms with opposite chirality are referred to as a "racemic mixture". The compound having more than one chiral center has 2n " 1 pair of enantiomers where n is the number of chiral centers. Compounds with more than one chiral center may exist as an individual diastereomer or as a mixture of diastereomers, called a "diastereomeric mixture". If the connection has one chiral center, the stereoisomer could be characterized by the absolute configuration of the chiral center. Absolute configuration means the way the space is arranged, the substitutes connected to the chiral center. The enantiomers are characterized by the absolute configuration of their chiral centers and described by the rules of the R- and S-sequences of Cane, Ingold and Preloga. The generally accepted rules of the stereochemistry nomenclature 12, the method for the detection of stereochemistry and the separation of stereoisomers are well known in the art (e.g., see " Advanced Organic Chemistry ", 4th ea'ition, March, Jerry, John Wiley & Sons, New York, 1992). It is clear that the names and illustrations used in this application to describe compounds of formula (I) contain all possible stereoisomers.

&Quot; Optional " or " optional " or " may be " means that, after these words, the event or circumstance may or may not occur, and that the description includes examples of when an event or circumstance occurs and examples of an event or the circumstance does not happen. For example, the words "wherein the aromatic ring Ra is optionally substituted with one or two substituents independently selected from alkyl" means that the aromatic ring may be substituted or may not be substituted by an alkyl group to match the scope of the invention.

The present invention also includes N-oxide derivatives of a compound of formula (I). An N-oxide derivative means a compound of formula (I) wherein the nitrogen atom is oxidized (i.e., N- * 0), for example, pyridine N-oxide, and which has the desired pharmacological activity.

Disease “pathology” means the essential nature of the disease, the causes and the development, as well as the structural functional changes that are the result of the disease processes.

&Quot; Pharmaceutically acceptable " means that if something is useful for the preparation of a pharmaceutical composition, it is usually also safe, non-toxic and not undesirable either biologically or otherwise and contains what is acceptable for veterinary use as well as human pharmaceuticals. for use.

&Quot; Pharmaceutically acceptable salt " means a salt of a compound of formula (I) which is pharmaceutically acceptable as defined above and which has the desired pharmacological activity. These salts contain acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with organic-acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentane propionic acid, glycolic acid, pervinic acid, oxypropionic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid , cinnamic acid, mandelic acid, methylsulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethylene sulphonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camparulfonic acid, 4-methylbicyclo [2.2.2] oct-2-en-1-carboxylic acid, glycoheptonic acid , 4,4'-methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butyl acetic acid, laurylic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also contain base addition salts which may be formed when the existing acid protons are capable of reacting with inorganic or organic bases. Acceptable inorganic bases contain sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium 13 13 LV 13669 hydroxide. Acceptable organic bases contain ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine and the like.

[0079] The present invention also includes the prodrugs of the compound of formula (I). Prose means a compound that is converted in vivo into a metabolic form (e.g., by hydrolysis) to form a compound of formula (I). For example, an ester of a compound of formula (i) that contains a hydroxyl group may be converted to the original formula by hydrolysis in vivo. Or, an ester of a compound of formula (I) containing a carboxyl group may be converted to the initial hydrolysis in vivo. Suitable esters of a compound of formula (I) containing a hydroxyl group include, for example, acetates, citrates, lactates, tartrates, malonate, oxalates, salicylates, propionates, succinates, fumarates, maleate, methylene bis-pb-hydroxynaphthates, gentisates, isothionates , di-p-toluene tartrates, methylsulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, and hexanes. Suitable esters of compounds of formula (I) containing a carboxyl group are described by Leinvveber, FJ. DrugMetab. Res., 1987, 18, page 379. Especially useful esters of compounds of formula (I) containing a hydroxyl group may be formed from acid functional groups selected from those described by Bundgaard et al., J. Med. Chem., 1989, 32, pp. 2503-2507, containing substituted (aminomethyl) benzoates, such as dialkylaminomethylbenzoates, in which two alkyl groups can be bonded and / or separated by an oxygen atom or an optionally substituted nitrogen atom such as an alkylated nitrogen atom; and more specifically (morpholymethyl) benzoates such as 3- or 4- (morpholinomethyl) benzoate and (4-alkylpiperazin-1-yl) benzoates such as 3- or 4- (4-alkylpiperazin-1-yl) benzoates.

&Quot; Protected Derivatives " means derivatives of compounds of formula (I) in which the reactive zone or zones are blocked by protecting groups. The protected derivatives of the compounds of formula (I) may be used in the preparation of compounds of formula (I) or may be active cathepsin S inhibitors themselves. An extensive list of suitable protective groups is listed in T. W. Greene, Protective Groupsin Organic Synthesis, 3rd edition,

John Wiley & Sons, Inc. 1999

&Quot; Therapeutically effective amount " means the amount that is sufficient for treating the disease for the animal to treat the disease.

&Quot; Treatment " or " treat " means any administration of a compound described in the present invention and comprising the following: (1) preventing the onset of disease in an animal that may be at the disposal of the disease but not yet experiencing or showing disease pathology or symptomology; ) the inhibition of disease in an animal suffering from or showing disease pathology or symptomology (ie preventing further development of disease pathology and / or 'symptomology'), or 14 (3) reduction of disease in an animal suffering from or showing disease pathology or symptomatic abnormalities (ie altering the disease) pathology and / or symptomatology). " Treatment " or " treat " with respect to combination therapy, i.e., when administered with the biological agents in combination with the invention described herein, comprises: (1) preventing an immune response in an animal that may have an immune response but not yet feeling or (2) inhibition of immune responses in an animal that is experiencing or exhibiting a pathological or symptomatic symptom of an immune response (ie preventing further development of pathology and / or symptomatology); or (3) reduction of immune response in an animal experiencing or exhibiting immunity. immune response pathology or symptomatology (ie to reduce the level or severity of the immune response, or the degree, or duration, manifestations, or alter the pathology and / or symptomology, for example, to reduce the binding and generation of antigenic antigens to MHC class II molecules, to reduce T-cell \ t and B-cell activation, reduced humoral reactions and reactions mediated by cells, and to reduce inflammation, blood flow, pain, necrosis, reduce the effectiveness of the biological product and the like, according to individual immune responses.

The words "wherein the aromatic or alicyclic ring RD is optionally substituted with one, two, or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy or halogen; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaryl, aralkyl, heteroaryl, aralkyl, heteroaralkyl , cycloalkyl, cycloalkylalkyl, ... " R5 in the definition of a compound of formula (I) means that all directly or indirectly attached aromatic and alicyclic rings R5 (e.g., R5 is cycloalkylcyclo, -alkylene-X-R9 wherein X is as defined in the Summary of the Invention, and R9 is aryl, aralkyl, and the like. ) 'Is optionally substituted with Ra, or Rb and Rc, or only with R °.

Preferred Embodiments of the Invention Preferred I. Preferred compounds of formula (I) are preferred in the broadest aspect of the invention. For instance:. (A) A preferred group of compounds is wherein: R 1 is hydrogen or methyl, preferably hydrogen; R2 is cyclopropyl, 1-phenylethyl [-0Η (06Η5) 0Η3], or 1H-pyrazo-5-yl; preferably cyclopropyl. 15 15 EN 13669 [0085] (1) In the aforementioned (A) group, which is preferred, and in the preferred group and belonging to group (A), the group of compounds that is preferred is where: R 3 is hydrogen and R 4 is alkyl, preferably methyl, ethyl, propyl or butyl, more preferably when R 4 is ethyl or propyl.

(2) In the above-mentioned group (A), which is preferred, and in the preferred group and belonging to the group (A), the group of compounds which is preferred above is where R 3 is alkyl, preferably methyl or ethyl and R4 is alkyl, preferably methyl, ethyl, propyl or buty, preferably R4 is methyl. Preferably R3 and R4 are methyl.

(3) In the above-mentioned group (A), which is preferred, and in the group which is preferred, and which belongs to group (A), the group of compounds which is preferred above is' where R3 and \ t R4 together with the carbon atom to which they are attached form cycloalkylene, preferably cyclopropylene, cyclopentylene or cyclohexylene, more preferably cyclopropylene.

(4) In the above-mentioned group (A), which is preferred, and in the preferred group, which belongs to group (A), the group of compounds which is preferred is where R3 and R4 are preferred. together with the carbon atom to which they are attached forms a piperidin-4-yl group in which the nitrogen atom is substituted with an arethyl group, 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl or 1,1-dioxotetrahydrothiopyran. -4-long group.

(I) In the above-mentioned groups (A) and A (1 -4), which are preferred, and in groups which are preferred, and belonging to those groups, the group of compounds which is preferred is wherein R6 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 1,1,2,2,3,3,3-heptafluoropropyl, and R7 and RB is hydrogen.

(Ii) In the above-mentioned groups (A) and A (1 -4), which are preferred, and in groups which are preferred, and which belong to the above groups, the group of compounds which is preferred is: where R 6 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, R 7 is haloalkyl, preferably trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2 , 2,2,2-pentafluoroethyl and R 8 are hydrogen.

(Iii) In the above-mentioned (A) and A (1 ~ 4) groups, which are preferred, and in groups which are preferred first and foremost, the group of compounds which is preferred is: wherein R8 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl; R7 is alkyl, preferably methyl, ethyl or propyl, and R8 is hydrogen. 16 (iv)] (iii) In the above-mentioned (A) and A (1-4) groups, which are preferred, and in the groups which are preferred, the group of compounds having preference is above all is where R6 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, R7 is haloalkyl, preferably trifluoromethyl or 2,2,2-trifluoroethyl and R 8 is aryl optionally substituted with one, two or three R 6. Better R8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-diphenorphenyl. More preferably, R 6 and R 7 are trifluoromethyl and R 8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4 or 3,5-diphenorphenyl.

(Iv) In the above-mentioned (A) and A (1-4) groups, which are preferred, and in groups that are preferred, the group of compounds that is preferred is that wherein R6 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,3-pentafluoroethyl, R7 is alkyl, preferably methyl or ethyl, and R8 is aryl which is optionally substituted by one, two or three Re. Better R8 is phenyl, 4-fluorophenyl, 2.3, 2,4, 2,5, 2,6, 3,4 or 3,5-difluorophenyl. More preferably, R 6 is trifluoromethyl and R 7 is methyl and R 8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, - or 3,5-difluorophenyl.

(V) In the above-mentioned groups (A) and A (1-4), which are preferred, and in groups which are preferred, and belonging to the above groups, the group of compounds which is preferred is where R6 is haloalkyl, preferably trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, R 'is hydrogen and R8 is aryl optionally substituted with one, two or three Rs . Better R8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl. Even more R 6 is trifluoromethyl and R 8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, - or 3,5-difluorophenyl, preferably 2 , 4-difluorophenyl.

(Vi) In the above-mentioned groups (A) and A (1-4), which are preferred, and in groups which are preferred, and which are attached to said groups, the preferred group of compounds is: where R6 is haloalkyl, preferably trifluoromethyl group 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, R7 is haloalkyl, preferably trifluoromethyl or 2,2,2-trifluoroethyl and R8 is heteroaryl optionally optional replaced by one, two or three Re. Better R8 is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl , imidazol-5-yl, pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimidine-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl, [ 1.2.3] Thiadiazol-4-yl, imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, thiazole-4 long group, thiazol-5-yl optionally substituted with one or two methyl groups.

(Vii) In the above-mentioned groups (A) and A (1-4), which are preferred, and in groups which are preferred, and which belong to those groups, the group of compounds which is preferred to the first group where R5 is haloalkyl, preferably trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, R7 is alkyl, preferably methyl or ethyl, and R8 is heteroaryl optionally substituted by one, two or three Re. Better R8 is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl , imidazol-5-yl, pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimidine-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl, [ 1.2.3] Thiadiazol-4-yl, imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrol-2-yl, pyrrole-3-yl, thiazole-4 long group, thiazol-5-yl optionally substituted with one or two methyl groups.

(Viii) In the above-mentioned groups (A) and A (1-4), which are preferred, and in groups which are preferred, and belonging to said groups, the group of compounds that is preferred is where R6 is haloalkyl, preferably trifluoromethyl group 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, R7 is hydrogen and R8 is heteroaryl optionally substituted with one, two or three Re Better R8 is indole -5-long group, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, imidazol-5 -yl, pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimidine-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl, [1.2.3 ] thiadiazol-4-yl, imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, thiazol-4-yl, thiazol-5-yl optionally substituted by one or di methyl groups, (a) above (A); In groups A (1-4), A (i-viii) and A (1-4) (i-viii), which are preferred, and in groups that are preferred to the first order, and belonging to said groups, the group of compounds, preferred, where R 5 is cycloalkylalkyl optionally substituted with one, two or three R 8 independently selected from alkyl or halogen or R c selected from aralkyl or heteroaralkyl, preferably 1-methylcyclopentylmethyl, 1-methylcyclopentylmethyl, 1-methylcyclopentylmethyl, 1-methylcyclohexylmethyl, 1-methylcyclohexylmethyl, 1-methylcyclohexylmethyl, 1-Methylcyclobutylmethyl, 1-methyl-3,3-difluoro-cyclobutylmethyl, 1-methyl-4,4-difluoro-cyclohexylmethyl, 1-benzylcyclopropylethyl, 1-thiazol-2-ylmethylcyclopropylmethyl, or 1-methyl-3,3-difluoro-cyclopentylmethyl.

(B)) Preferred groups (A), A (1-4), A (i-viii) and A (i-4) (i-viii) above and groups preferred first and foremost of these groups, the more preferred group of compounds is where R5 is alkyl, preferably 2,2-dimethylpropyl, 3,3-dimethylpentyl, 2,2,3,3-tetramethylbutyl.

(C)) Preferred groups (A), A (1 -4), A (i-viii) and A (i-4) (i-viii) above and groups preferred first and foremost of these groups, a group of compounds having even greater preference is wherein R5 is haloalkyl, preferably 2,2-dichloroethyl, 3,3,3-trifluoropropyl, 2,2-trifluoromethylethyl or 2.2, 2-trifluoroethyl.

1S

(D)) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above and preferred groups first and foremost of these groups, the more preferred group of compounds is where R5 is haloalkoxy substituted with aryl, heteroaryl or heterocycloalkyl, preferably 2,2-difluoro-3-phenylpropyl, 2,2- difluoro-3-tetrahydropyran-4-ylpropyl, 2,2-difluoro-3-morpholin-4-ylpropyl, 2,2-difluoro-3-pyridin-2-ylpentyl, 2,2-difluoro-3-pyridin-3-yl ilpropyl or 2,2-dichloro-3-phenylpropyl.

(E)) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above, and groups preferred first and foremost of these groups, a group of compounds having an even greater preference is wherein R5 is an arylalkyl optionally substituted by one, two or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halogen; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, neteroaryl, arylalkyl , cycloalkyl, cycloalkylalkyl, heierocikloalkilgrupas, heterocycloalkylalkyl, acyl, aryloxycarbonyl, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, heterocikloalkiloksikarbonilgrupas, aryloxy, heteroariioksigrupas, aralkyloxy, heteroaralkiloksigrupas, aminokarboniigrupas aminosulfonyl or -S02R11 (kurR11 iralkilgrupa, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl); and also wherein the aromatic or alicyclic ring Rc is optionally substituted by one, two or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy or halogen. Better R5 is benzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, 2-chlorobenzyl, 4-ethoxybenzyl, biphen-4-ylmethyl, naphth-1-ylmethyl, naphth-2-ylmethyl, 4-chlorobenzyl, 3-chlorobenzyl, 4 fluorobenzyl, 2-phenethyl, 4-hydroxybenzyl, 2- (4-hydroxyphenyljetyl, 2,6-difluorobenzyl, biphenyl-3-ylmethyl, 3-phenylpropyl or 2,2-dimethyl-3-phenylpropyl. Preferably R3 is 2-chlorobenzyl) , 3-chlorobenzyl or 4-fluorobenzyl.

(F) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above and groups that are preferred first and those belonging to said groups, the more preferred group of compounds is where R5 is a heteroaralkyl optionally substituted with one, two or three Rs independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano or halogen; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl,. 19 19 EN 13669, aralkyl, heteroaralkyl, cycloalkyl, cikloalkilalkilgmpas, heterocikloafkilgrupas, heterocycloalkylalkyl, acyl, aryloxycarbonyl, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, aryloxy, heteroariioksigrupas, aralkyloxy, heteroaralkiloksigrupas, aminocarbonyl, aminosulfonyl or -S02R11 (kurR11 is alkyl, aryl, heteroaryl, or heterocikioalkilgrupa ); and also wherein the aromatic or alicyclic ring Rc is optionally substituted by one, two or three Rd independently selected from an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, a haloalkoxy group or a halogen. Preferably R5 is 2-bromo-thiophen-5-ylmethyl, pyridin-4-ylmethyl or 2-dimethyl-3-pyridin-3-ylpropyl.

(G) the preferred (A), A (1-4), A (i-viii) and A (1-4) (i-viii) groups preferred and in groups preferred first and foremost of these groups, the more preferred group of compounds is where R5 - (alkylene) -S (O) 2-R9, wherein R9 is alkyl, preferably R5 is methylsulfonylmethyl, ethylsulfonylmethyl, propyl 1-sulfonylmethyl, 2-methylpropylsulfonylmethyl, 2-methylsulfonyl or 2-ethylsulfonyl group.

(H)) preferred groups (A), A (1-4), A (i-viii), and A (1-4) (viii) above, and groups preferred first and foremost of these groups, a group of compounds having a greater preference for lysis is wherein R 3 is - (alkyl) -S (O) 2 R 9, wherein R 9 is an aryl group or an aryl group optionally substituted by one, two or three Ra independently selected from an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, a haloalkoxy group, a cyano group or a halogen; or optionally replaced by. one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaryl, cycloalkyl, cycloalkyl, aralkyl, heteroaryl, cycloalkyl, cikloalkilalkilgmpas, heterocikloaikilgrupas, heterocycloalkylalkyl, acyl, ariloksikarboniigrupas, aralkiioksikarboniigrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, aryloxy, heteroariioksigrupas, aralkyloxy, heteroaralkiloksigrupas, aminocarbonyl, aminosulfonyl or -S02R11 (wherein R11 is alkyl, aryl, heteroaryl, or heterocikioalkilgrupa); and also wherein the aromatic or alicyclic ring Rc is optionally substituted with one, two or three Rd independently selected from an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyl group, a haloalkoxy group or a halogen. Better R5 is 2-difluoromethoxyphenimethanesulfonylmethyl, 2-phenylsulfonylmethyl, 4-fluorophenylmethanesulfonylmethyl, 4-aminocarbonylphenylmethanesulfonylmethyl, 4-piperazin-1-ylmethane, methylmethyl, 2-fluorophenylmethanesulfonylmethyl, 3-fluorophenylmethanesulfonylmethyl, 2.4.6 trifluorophenylmethanesulfonylmethyl, 2-, 3- or 4-trifluoromethylphenylmethanesulfonylmethyl, phenylmethanesulfonylmethyl, 2- (2-, 3- or 4-trifluoromethylphenyl) sulfonethyl or 2- (2-, 3- or 4-fluorophenyl) sulfonyl group. 20 (i)) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above, and groups preferred preferred and belonging to said groups, the more preferred group of compounds is where R5 is - (alkylene) -S (O) 2-R9, wherein R9 is a heteroaryl or heteroaralkyl optionally substituted with one , two or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy, cyano or halo; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaryl, aralkyl, heteroaralkyl , cycloalkyl, cycloalkylalkyl, heterocycloalkyl heterocikioalkilalkilgrupas, acyl, aryloxycarbonyl, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heieroaralkiloksikarbonilgrupas, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkiloksigrupas, aminocarbonyl, aminosulfonyl or -SO2R11 (kurR11 is alkyl, aryl, heteroaryl, or heterocycloalkyl); and also wherein the aromatic or alicyclic ring Rc is optionally substituted with one, two or three R 0 independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy or halogen. More preferably R ° and pyridin-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-ylmethanesulfonylmethyl, 3-difluoromethoxypyridin-2-ylmethanesulfonylmethyl, 2-difluoromethoxypyridin-3-ylmethanesulfonylmethyl, 4-difluoromethoxypyridin-3-ylmethanesulfonylmethyl, 3- difluoromethoxypyridin-4-ylmethanesulfonylmethyl, pyrimidin-2-ylmethanesulfonylmethyl, pyrimidin-5-ylmethanesulfonylmethyl, 3-trifluoromethylpyridin-2-ylmethanesulfonylmethyl, 4-trifluoromethylpyridin-3-ylmethanesulfonylmethyl, 3,5-dimethylisoxazol-4-ylmethanesulfonylmethyl, 2-fluoromethanesulfonylmethyl, 2-fluoromethan-5-ylmethanesulfonylmethyl; -ylmethanesulfonylmethyl, 2-methylthiazol-4-ylmethanesulfonylmethyl, furan-2-ylmethanesulfonylmethyl, 2-pyridin-2-ylethanesulfonylmethyl, 2-pyridin-3-ylethanesulfonylmethyl, 2-pyridin-4-ylethanesulfonylmethyl, 2-pyridin-3-ylsulfonylmethyl, 2-Pyridin-4-ylsulfonyl-ethyl, 3-pyridin-3-ylsulfonylpropyl, 1,3,5-triazin-2-ylmethanesulfonylmethyl, 1,3,4-thiadiazol-2-expression thanesulfonylmethyl, oxazol-5-ylmethanesulfonylmethyl, thiazol-5-ylmethanesulfonylmethyl or thiazol-2-ylmethanesulfonylmethyl.

0) Preferred groups (A), A (1-4), A (i-viii) and A (1-4) (i-viii) above, and groups that are preferred above and belonging to said groups, the more preferred group of compounds is where R5 is - (alkylene) -S (O) 2-R9, wherein R9 is heterocycloalkyl or heterocycloalkylalkyl optionally substituted with one, two or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy, cyano or halo; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxyl or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, 21 21 LV 13669, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, ariloksikarboniigrupas, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkiloksikarbonilgrupas, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkiloksigrupas, aminocarbonyl, aminosulfonyl or -SO2R11 (wherein R11 iralkilgrupa, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl) ; and also wherein the aromatic or alicyclic ring Rc is optionally substituted with one, two or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halogen. Better R5 is piperidin-1-ylsulphonylmethyl or piperidin-4-ylmethanesulfonylphenyl, where the nitrogen atom in the piperidine ring is substituted with methyl, ethyl, azoethyl, methylsulfonyl or aminosulfonyl, tetrahydropyran-4-ylsulfonylmethyl, fetrahydropyran-4-ylsulfonylmethyl, 1,1-dioxotetrahydrothiopyran; 4-ylmethanesulfonylmethyl or morpholin-4-ylmethanesulfonylmethyl.

(K) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above, and groups preferred first and those belonging to said groups, the more preferred group of compounds is where R5 is - (alkylene) -S (O) 2-R8, wherein R9 is cycloalkylalkyl, preferably R5 is cyclopropylmethylsulfonylmethyl.

(1) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above, and groups preferred belonging to the mentioned groups, R5 is ethylsulfonylmethyl, 2-methylsulfonylmethyl, 2-methylpropylsulfonylmethyl, benzenesulfonylmethyl, 2-phenylsulfonylmethyl, naphth-2-ylmethanesulfonylmethyl, biphenyl-2-ylmethanesulfonylmethyl, biphenyl-4-ylmethanesulfonylmethyl, biphenyl-4-ylmethanesulfonylmethyl, phenylmethanesulfonylmethyl, -2-phenylmethanesulfonylmethyl, -2-phenylmethanesulfonylmethyl, 4-tert-butilfenilmetānsulfonilnetilgrupa, 2-fluorfenilmetānsulfonilmetilgrupa, 3-fluorfenilmetānsulfoniimetilgrupa, 4-fluorfenilmetānsulfonī! methyl 2-hlorfenilmetānsulfonilmetilgrupa, 3-hlorofenilmetānsu! backgrounds! methyl 4-hlorfenilmetānsulfonilmetilgrupa, 2-metoksifenilmetānsulfonilmetilgrupa, 4-metoksifenilmetānsulfonilmetilgrupa, 2-trifiuormetoksifenilmetānsulfonilmetil-group 3-Trifluoromethoxyphenylmethanesulfonylmethyl, 4-trifluoromethoxyphenylmethane fonilmetilgrupa, 2-trifluormetilfenilmetānsulfonilmetilgrupa, 3-trifluormetilfenilmetānsulfonilmetilgrupa, 4-trifluormetilfenilmetānsulfonilmetilgrupa, 2-ciānofenilmetānsulfonilmetilgrupa, 3-ciānofenilmetānsulfonilmetilgrupa, 2-bromfenilmetānsulfonilmetilgrupa 2- methylphenyl metānsuifonilmetilgrupa-3-metilfenilmetānsulfonilmetilgrupa, 4-metilfenilmetānsulfonilmetilgrupa, 2- (4-trifluormetoksibenzolsulfonil ) ethyl, 2- (3-trifluoromethoxybenzenesulfonyl) ethyl, 2- (2-trifluoromethoxy-. benzenesulfonyl) ethyl, 2-difluoromethoxyphenylmethanesulfonyl-ethyl, 3-difluoromethoxyphenylmethanesulfonylmethyl, 4-difluoromethoxyphen (methanesulfones (methyl, 2- (4-difluoromethoxybenzenesulfonyl) ethyl, 2- (2-difluoromethoxybenzenesulfonyl) ethyl, 2- ( 3-Difluoromethoxybenzenesulfonyl) ethyl, 3-chloro-2-fluorophenylmethanesulfonylmethyl, 3,5-dimethylphenylmethanesulfonylmethyl, 3,5-bis-trifluoromethylphenylmethanesulfonylmethyl, 2,5-difluorophenylmethanesulfonylmethyl, 2,6-difluorophenylmethanesulfonylmethyl, 2,3-difluorophenyl-22-methanesulfonylmethyl, , 3,4-Diphenylphenylmethanesulfonylmethyl, 2,4-difluorophenylmethanesulfonylmethyl, 2,5-dichlorophenylmethanesulfonylmethyl, 3,4-dichlorophenylmethanesulfonylmethyl, 2,6-dichlorophenylmethanesulfonylmethyl, 2-fluoro-3-methylphenylmethanesulfonylmethyl, 4-fluoro-2-trifluoromethoxyphenylmethanesulfonylmethyl, 2 -fluoro-6-fluorofluoromethylphenylmethanesulfonylmethyl, 2-fluoro-3-trifluoromethylphenylmethanesulfonylmethyl, 2- fluoro-4-trifluoromethylphenylmethanesulfonylmethyl, 2-fluoro-5-trifluoromethylphenylmethanesulfonylmethyl, 4-fluoro-3-trifluoromethylphenylmethanesulfonylmethyl, 2-chloro-5-trifluoromethylphenylmethanesulfonylmethyl, 2,4,6-trifluorophenylmethanesulfonylmethyl, 2,4,5-trifluoromethylmethanesulfonylmethyl, , 3,4-Trifluorophenylmethanesulfonylmethyl, 2,3,5-trifluorophenylmethanesulfonylmethyl, 2,5,6-trifluorophenylmethanesulfonylmethyl, 3,4,5-trimethoxyphenylmethanesulfonylmethyl, pyridin-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-yl Methanesulfonylmethyl, 2- (pyridin-2-ylsulfonyl) -yl, 2- (pyridin-4-ylsulfonyl) ethyl, oxypyridin-2-ylmethanesulfonylmethyl, cyclohexylmethanesulfonylmethyl, cyclohexylmethanesulfonylmethyl, cyclopropylmethanesulfonylmethyl, 5-chlorothene-2-sulfonylmethyl, 5-chlorothiene-2 -ylmethanesulfonylmethyl or 3,5-dimethylisoxazol-4-ylmethanesulfonyl] group.

(M) Preferred groups (A), A (1-4), A (i-viii), and A (1-4) (i-viii) above, and groups that are preferred first belonging to the groups mentioned, R ° is 1-ethoxycarbonone [piperidin-4-ylmethyl, 1-methylpiperidin-4-ylmethyl, 2-teirahydropyram-4-yl-ethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl, morpholine -4-ylmethyl, 2-morpholin-4-yl-ethyl, thiomorpholin-4-yl-ethyl, 1-oxo-thiomorpholin-4-ylamyl, 1,1-dioxothiomorpholin-4-ylmethyl, tertiary hydropyran-4-ylmethyl, 1-oxotetrahydrothiopyran-4 -ylmethyl, 1,1-dioxoteirahydrothiopyran-4-ylmeyl, 1-methylpiperazin-4-ylmeyl, benzyloxymethyl, ethoxymethyl, isopropyloxymethyl radical, 2-piperidin-1-yl-ethyl, 2-pyrrolidin-1-ylethyl, tert-butyloxymethyl, imidazole 4-ylmethyl, indol-3-ylamyl, indol-2-ylmethyl, 1-benzylimidazol-4-ylmethyl; 4-ethyl-4-methylpiperidin-1-ylmethyl, indol-1-ylmethyl, 1-methylpiperidin-2-ylmethyl, 2,2, -difluoro-3-thien-2-ylmethyl or pyridin-4-ylmethyl.

(N) The above-mentioned (A), A (1-4), A (vi-vi) and A (1-4) (i-viii) preferred groups and first-to-first groups belonging to the mentioned groups, R5 is 3,5-dimethylisoxazol-4-ylmethanesulfonylmethyl, 2-CF3methylphenylmethanesulfonylmethyl, 3-CF3pyridin-2-ylmethanesulfonylmethyl, 2-F-furan-5-ylmethanesulfonylmethyl, 2-methylthiazolyl 4-ylmethanesulfonylmethyl, tetrahydropyran-4-ylmethanesulfonylmethyl, 1,1-dioxo-1A6-hexahydro-thiopyran-4-ylmethanesulfonylmethyl, 1-ethylpiperidin-4-ylmethanesulfonylmethyl, 2-oxotetrahydropyrimidin-4-ylmethanesulfonylmethyl, 1-ethyl-2-oxopiperidinyl 4-ylmethanesulfonylmethyl, 1-acetylpiperidin-4-ylmethanesulfonylmethyl, 1-ethoxycarbonylpiperidin-4-ylmethanesulfonylmethyl, 1-methylsulfonylpiperidin-4-ylmethanesulfonylmethyl, 1-cyclopropylpiperidin-4-ylmethanesulfonylmethyl, 1-acetyl azetidin-3-ylmethanesulfonylmethyl, 1-ethoxycarbonyl azetidin-3-ylmethyl, year n-sulfonylmethyl, 1-methylsulfonylazetidin-3-ylmethanesulfonylmethyl, 1-ethylazetidin-3-yl-23,213,139,9-methanesulfonylmethyl, 1-cyclopropylazetidin-3-ylmethanesulfonylmethyl, furan-2-ylmethanesulfonylmethyl, difluoro- (4-fluorophenyl) methanesulfonylmethylgmpa, pyrazin-2-yl) methanesulfonylmethyl, difluoro- (2-difluoromethoxyphenylmethanesulfonylmethylgmpa, 1-acetylpiperidin-4-yl) sulfonylmethyl, 1-ethoxycarbonylpiperidin-4-ylsulfonylmethyl, 1-cyclopropylpiperidin-4-ylsulfonylmethyl, 2- (pyridin-2-yl) ) ethanesulfonylmethyl, 2- (pyridin-3-yl) ethanesulfonylmethyl, 2- (pyridin-4-yl) ethanesulfonylmethyl, 3- (pyridin-2-ylpropane sulfonylmethyl, 2,6-difluorophenylmethanesulfonyl, [1,3,5] triazin-2-ylmethanesulfonylmethyl) [1.3.4] Thiadiazol-2-ylmethanesulfonylmethyl, oxazol-5-ylmethanesulfonylmethyl, thiazol-5-ylmethanesulfonylmethyl, 4-fluorophenylmethanesulfonylmethyl, 4-aminocarbonylphenylmethanesulfonylmethyl, 4-piperazin-4-ylphenyl methanesulfonylmethyl, 5-fluoroindo (-3-ylmethanesulfonylmethyl, 4,6-difluorindol-3-ylmethanesulfonylmethyl, 1-methylindol-3-ylmethanesulfonylmethyl, 4-fluoroindol-3-ylmethanesulfonylmethyl, 2- (5-fluoroindol-3-yl) ethanesulfonylmethyl, 2- (4,6-Difluoroindol-3-yl) ethanesulfonylmethyl, 2- (1-methylindol-3-yl) ethanesulfonylmethyl, 2- (4-fluoroindol-3-yl) ethanesulfonylmethyl, 2-quinolin-3 -ilyansulfonylmethyl, 2-quinolin-2-ylethanesulfonylmethyl, isoquinolin-3-ylmethanesulfonylmethyl, 2- (isoquinolin-3-yl) ethanophenylmethyl, 2,4-difluoropyridin-3-ylmethanesulfonylmethyl, 3,4-difluoropyridin-4-one 2- (2,4-difluoropindin-4-yl) ethanesulfonylmethyl, fluoro (N, N-difluoropyridine-5-ylmethanesulfonylmethyl, fluoro) (3,4-difluoropyridin-5-ylmethanesulfonylmethyl); -difluoropyridin-4-yl) methanesulfonylmethyl, 2,4-diCF3-pyridin-3-ylmethanesulfonylmethyl, 3,4-diCF3-pyridin-4-ylmethanesulfonylmethyl, 2- (2,4-diCF3-pyridin-3-yl) -ethanesulfonyl Methyl, 2- (3,4-diCF3-pyridin-4-yl) ethanesulfonylmethyl, fluoro- (2,4-diCF3-pyridin-3-yl) -methanesulfonylmethyl, fluoro- (3,4-diCF3-pyridin-4-yl) -methanesulfonylmethyl, 4 -F-pyridin-3-ylmethanesulfonylmethyl, 3-F-pyridin-5-ylmethanesulfonylmethyl, 2-F-pyridin-5-ylmethanesulfonylmethyl, 2- " F-pyridin-3-ylmethanesulfonylmethyl, 5-F-pyridin-2-ylmethanesulfonylmethyl 4-F-Pyridin-2-ylmethanesulfonylmethyl, 4-F-1-oxopyridin-3-ylmethanesulfonylmethyl, 3-F-1-oxopyridin-5-ylmethanesulfonylmethyl, 2-F-1-oxopyridin-5-ylmethanesulfonylmethyl, 2-F 1-Oxopyridin-3-ylmethanesulfonylmethyl, 5-F-1-oxopyridin-2-ylmethanesulfonylmethyl, 4-F-1-oxopyridin-2-ylmethanesulfonylmethyl, 4-CF 3-pyridin-2-ylmethylsulfonylmethyl, 3-CF 3-pyridin-5 -ylmethanesulfonmethyl, 3- F-pyridin-2-ylmethanesulfonylmethyl, 2-CF 3-pyridin-3-ylmethanesulfonylmethyl, 4-CF 3 -1-oxopyridin-2-ylmethanesulfonylmethyl, 3-CF 3 -1-oxopridin-5-ylmethanesulfonylmethyl , 3- F-1-oxopyridin-2-ylmethanesulfonylmethyl, 2-CF 3 -1-oxopyridin-3-ylmethanesulfonylmethyl, 5-CF 3 -1-oxopyridin-2-ylmethanesulfonylmethyl, 2-CH 3 -pyridin-6-ylmethanesulfonylmethyl, 3-CH 3 pyridin-2-ylmethanesulfonylmethyl, 4-CH3-pyridin-3-ylmethanesulfonylmethyl, 3-CH3-pyridin-4-ylmethanesulfonylmethyl, 2- (2-CFt3-pyridin-6-yl) ethanesulfonylmethyl, 2- (3-CF3-pyridine) -2-yl) ethanesulfonylmethyl, 2- (4-CF3-pyridin-3-yl) ethanesulfonylmethyl, 2- (3-CF3-pyridin-4-yl) ethanesulfonylmethyl, 2-C2H5-Surin-6-ylmethanesulfonylmethyl, 3- C2H5 - pyridin-2-ylmethanesulfonylmethyl, 4-C2F15-pyridin-3-ylmethanesulfonylmethyl, 3-C2H5-pyridin-4-ylmethanesulfonylmethyl, 2- (2-C2F15-pyridin-6-yl) ethanephonylmethyl, 2- (3-C2H5-pyridine -2-yl) ethanophenylmethyl, 2- (4-C2F15-pyridin-3-yl) ethanesulfonylmethylgmpa, 2- (3-24C2H5-Surin-4-yl) ethanesulfonimide, 2- (2- CH3-Pyridin-3-yl) ethanesulfonylmethyl, 2-CF3-pyridin-3-ylmethanesulfonylmethyl-methyl-2- (3-CF) 3-Pyridin-4-yl) ethanesulfonylmethyl, 3-CF 3-pyridin-4-ylmethanone-phononyl, cinnolin-3-ynylfiphenylmethyl, 2- (cinnolin-3-yl) ethanesulfonylmethyl, phthalazin-1-ylmethanesulfonylmethyl, 2- (phthalazine) -1-yl) ethanephiphenylmeyl, 2- (henoxyn-2-yl) ethanesulfonylmethyl, quinazolin-2-ylmethanesulfonylmethylgmpa, 2- (quinazopin-2-yl) efanesulfonyl, ethyl, [1,8] naphthyridin-2-ylmethanesulfonylmethyl, 2- ([1,8] naphthyridin-2-yl) ethanesulfonylmethyl, [1,8] naphthyridin-3-ylmethanesulfonylmethyl, 2- ([1,8] naphthyridin-3-yl) ethanesulfonylmethyl, 3-Cl-pyridinyl 2-ylmethanesulfonylmethyl, 4-Cl-pyridin-3-ylmethanesulfonylmethyl, 3-Cl-pyridin-4-ylmethanesulfonomethyl, 3-F-pyridin-2-ylmethanesulfonylmethyl, 4-F-pyridin-3-ylmethanesulfonylmethyl-3-pyridin-3-yl-pyridine -4-ylmethanesulfonylmethyl, isoquinoin-4-methanesulfonylmethyl, 6-phenylpyridin-2-ylmethanesulfonylmethyl, 3-phenyl [pyridin-2-yl] -methanesulfonylmethyl, 4-phenylpyridin-2-ylmethanesulfonylmethyl α, 3-phenylpyridin-4-ylmethanesulfonylmethyl, 2- (6-phenylpyridin-2-yl) ethanesulfonylmethyl, 2- (3-phenylpyridin-2-yl) pyranophenylmethyl, 2- (4-phenylpyridin-3-yl) ethanesulfonylmethyl , 2- (3-Phenylpyridin-4-yl) ethanesulfonylmeyl, 6- (pyridin-2-yl) pyridin-2-ylmethanesulfonylmethylglyn, 3- (pyridin-2-yl) pyridin-2-ylidenhanesone. - (pyridin-2-yl) quinolin-3-ylmethanesulfonylmethyl, 3- (pyridin-2-yl) pyridin-4-yl [methanesulfonylmethyl, 2- [6- (pyridin-2-yl) surfin-2-one [] Ethanesulfonylmethyl, 2- [3- (pyridin-2-yl) pyridin-2-yl] sulfonylmethyl, 2- [4- (pyridin-2-yl) pyridin-3-yl] ethanesulfonylmethyl, 2- [3- (pyrid! n-2 - (pyridin-4-yl) -ansulfonylmethyl, 6- (pyridin-3-yl) pyridin-2-ylmethanesulfonylmethyl, 3- (pyridin-3-yl) pyridin-2-yl (methylsulfonylmethyl); - (Surin-3-yl) Surin-3-ylmethanesulfonylmethyl, 3- (pyridin-3-yl) pyridin-4-ylmethanesulfonylmethyl, 2- [6- (pyridin-3-yl) pyridin-2-yl] pyranphonylmethyl, 2- [3- (pyridin-34l) pyridin-24l] ethanesulronil methyl, 2- [4- (pyridin-3-yl) pyridin-2-yl] ethanesulfonylmethyl, 2- [3- (pyridin-3-yl) pyridin-4-yl] ethanesulfonylmethyl, 6- (quinolin-4-yl) pyridine -2-ylmethanulfonylmethyl, 3- (pyridin-4-yl) pyridin-2-ylmethanesulfonylmethyl, 4- (pyridin-4-yl) pyridin-3-ylmethanesulfonylmethyl] -13- (pyridin-4-yl) -pyridin-44lmethanesulfonylmethyl, 2- [6- (Pyridin-4-yl) pyridin-2-yl] ethanesulfonylmethyl, 2- [3- (pyridin-4-yl) pyridin-2-yl] ethanesulfonylmethyl, 2- [4- ( pyridin-4-yl) pyridin-3-yl] ethanesulfonylmethyl-2- [3- (pyridin-4-yl) pyridin-4-yl] ethanesulfonylmethyl, 2,2-dimethylcyclopropylmethanesulfonyl, biphen-2-ylmethanesulfonyl, 2-thiophen-2 Phenylmethanesulfonyl, 2-thiazol-2-ylphenylmethanesulfonyl, 2-thiazol-5-ylphenylmethanesulfonyl, 2- [1,2,3] thiazol-5-ylphenylmethanesulfonyl, 2-oxazol-5-ylphenylmethanesulfonyl, 2- (1-methylpyrazol-5-yl) ) phenylmethanesulfonyl radical, 2- [1.2.3] triazol-5-ylphenylmethanesulfonyl, 2- [1.2.3] oxadiazol-5-iphenylmethanesulfonyl upa, 2 - [(1.2.3) triazol-5-yl] phenylmethanesulfonylgmpa, 2 - [(1.2.3) triazol-1-yl] phenylmethanesulfonyl, oxo [5,4-b] pyridin-2-ylmethanesulfonylmethyl, oxazole [4 5-c] pyridin-2-ylmethanesulfonylmethyl, oxazolo [4,5-b] pyridin-2-ylmethanone [phenylmethyl, benzimidazol-5-ylmethanesulfonylmethyl, benzimidazol-4-ylmethanesulfonylmethyl, 3H-imidazo [4,5- b] pyridin-2-ylmethanesulfonylmethyl, 3H-imidazo [4,5-c] pyridin-2-ylmethanesulfonylmethyl, 3-CF3-3H-imidazo [4,5-b] pyridin-2-ylmethanesulfonylmethyl, 3-CF3-3H- ε-azazo [4,5-c] pyridin-2-ylmethanesulfonylmethyl, 2525 [deg.] 13669 1-CF3-1Frnidazo [4,5-c] pyridin-2-ylmethanesulfonylmethyl, 1-CF3-1H-imidazo [4,5-b ] pyridin-2-ylmethanesulfonylmethyl, thiazol [5,4-b] pyridin-2-methanesulfonylmethyl, thiazole [4,5-c] quinolin-2-ylmethanesulfonylmethyl, thiazole [4,5-b] pyridin-2-ylmethanesulfonylmethyl, 5-CF3-thiazole [534-b] pyridin-2 - (] methanesulfonylmethyl, 4-CF3-thiazole [4,5-c] pyridin-2-ylmethanesulfonylmethyl [group, 7-CF3] Thiazol [4,5-b] pyridin-2-ylmethanesulfonylmethyl, 3-CF3-1H-pyrido [233-b] pyridin-2-ylmethanesulfonylmethyl, 3-CF3-1H-pyrrolo [3,2-c] pyridine -2-methanesulfonylmethyl, 3-CF3-1H-pyrrolo [3,2-b] pyridin-2-ylmethanesulfonylmethyl, imidazo [1,2-c] pyrimidin-2-methanesulfonylmethyl, 8-CF3-imidazo [1,2-c] pyrimidin-2-methanesulfonylmethylgmpa, imidazo [1,2-a] pyrimidin-2-methanesulfonylmethyl, 8-CF3-imidazo [1,2-b] pyridazin-2-methanesulfonylmethyl, imidazo [1J2-a] pyrazin-2-methanesulfonyl [ methyl, 8-CFs-imidazofl-1-pypyrazin-4-methanesulfonylmethyl, pyrazolo [1,5-c] pyrimidin-2-ylmethanesulfonylmethyl, 3-CF3-pyrazolo [1,5-c] pyrimidin-2-ylmethanesulfonylmethyl, 4-CF3 pyrazolo [1,5-c] pyrimidin-2-ylmethanesulfonylmethyl, imidazo [1,2-d] [1,2,4] triazine-2-methanesulfonylmethyl, 3-CF3-imidazo [1,2-d] [ 1,2,4] Triazine-2-methanesulfonylmethyl, [1.3] benzoxazol-2-ylmethanesulfonylmethyl, 5-F- [1,3] benzoxazol-2-ylmethanesulfonylmethyl, [1,3] benzoxazol-4-ylmethanesulfonyl Ethyl, 2-CF 3 - [1,3] benzoxazol-4-ylmethanesulfonylmethyl, [1,3] benzoxazol-7-ylmethanesulfonylmethyl, 2-CF 3 - [1,3] benzoxazol-7-ylmethanesulfonylmethyl, [1,2] benzoxazole -3-ylmethanesulfonylmethyl. [1,2] Benzoxazol-4-ylmethanesulfonylmethyl, 5-CF3- [1,2] benzoxazol-4-ylmethanesulfonyl-ethyl, 3-CF3- [1,2] benzoxazole-4-enefan [Backgrounds (Group, 6-CF3) - [1,2] benzoxazol-7-ylmethanesulfonylmethyl, 6-CN- [1,2] benzoxazol-7-ylidenesulfonylmethyl, 3-CF3- [1,2] benzoxazol-7-ylmethanesulfonylmethyl, 5-F- [1] 2] benzoxazol-3-ylmethanesulfonylmethyl, [2.3] benzoxazol-7-ylmethanesulfonylmethyl, 6-CF3- [2,3] benzoxazol-7-ylmethanesulfonylmethyl, 1-CF3- [2,3] benzoxazol-7-ylmethanesulfonylmethyl, 5- CF3- [2,3] benzoxazol-4-ylmethanesulfonylmethyl, 5- CN- [2,3] benzoxazol-4-ylmethanesulfonylmethyl, 1-CF3- [2,3] benzoxazol-4-ylmethanesulfonylmethyl, benzothiazol-2-ylmethanesulfonylmethyl, 5 -F-benzothiazol-2-ylmethanesulfonylmethyl, benzothiazol-4-ylmethanesulfonylmethyl, 2-CF3-benzothiazol-4-ylmethanesulfonylmethyl, benzothiazol-7-ylmethanesulfonylmethyl, 2-CF3-benzothiazol-7-ylmethanesulfonylmethyl, [1,2] benzothiazol-3-yl ylmethanesulfonylmethyl, [1,2] benzothiazol-4-ylmethanesulfonylmethyl, 5-CF 3 - [1,2] benzothiazol-4-ylmethanesulfonylmethyl, 3-CF 3 - [1,2] benzothiazol-4-ylmethanesulfonylmethyl, 6- CF 3 - [1,2] benzothiazol-7-ylmethanesulfonylmethyl, 6-CN- [1,2] benzothiazol-7-ylmethanesulfonylmethyl, 3 -CF 3 - [1,2] benzothiazol-7-ylmethanesulfonylmethyl, 5-F- [1,2] benzothiazol-3-ylmethanesulfonylmethyl , [2,3] benzothiazol-7-ylmethanesulfonylmethyl, 6-CF 3 - [2,3] benzothiazol-7-ylmethanesulfonylmethyl, 1-CF 3 - [2,3] benzothiazol-7-ylmethanesulfonylmethyl, 5'CF 3 - [2,3 ] benzothiazol-4-ylmethanesulfonylmethyl, 26,5-CN- [2,3] benzothiazol-4-ylmethanesulfonylmethyl [group, 1-CF3- [2,3] benzothiazol-4-ylmethanesulfonylmethyl, 4-CF3-2-CH3- thiazol-5-ylmethanesulfonylmethyl, 4-CF 3 -thiazol-5-ylmethanesulfonylmethyl, 4-CF 3 -2-phenyl-thiazol-5-ylmethanesulfonylmethyl, 5-CF 3 -2-CH 3 -thiazol-4-ylmethanesulfonyl [methyl, 5-CF 3 - 2-Phenyl-thiazol-4-ylmethanesulfonylmethyl, 5-CH3-thiazol-2-ylmethanesulfonylmethyl, 5-CF3-thiazol-2-one sulfonylmethyl, 5-phenyl-thiazol-2-ylmethanesulfonylmethyl, 4-CH3-thiazol-2-ylmethanesulfonylmethyl, 4-CF3-thiazol-2-ylmethanone] phenylmethyl, 4-phenylthiazol-2-ylmethanesulfonylmethyl, 5-CH3-2- (Pyridin-2-yl) - [1,233] triazol-4-ylmethanesulfonylmethyl, 5-CF3-2- (quinolin-2-yl) - [1,2,3] ßππζ-4-ylmethanesulfonylmethyl 5-CF3-2- ( 4-Methylsulfonylphenyl) - [1,2,3] triazol-4-ylmethanesulfonylmethyl, 4,5-dimethyl- [1,2,4] triazol-3-ylmethanesulfonylmethyl chloride, 5-CF3-4-CH3- [ 1.2.4] iriazol-3-ylmethylphenylmethyl, 4-CH3-5-phenyl- [1,2,4] triazol-3-ylsulfonylmethyl, 5-CF3-4-cyclopropyl- [112,4] triazole-3 -ylmethanesulfonylmethyl, 2,5-dimethyl- [1.2.4] triazol-3-ylmethanesulfonylmethyl-glucose, 5-CF3-2-CH3- [1,2,4] triazol-3-ylmethanesulfonylmethyl, 2- CFl3-5 -phenyl- [1,2,14] triazol-3-ylidene-sulfonylmethyl-2-cyclopropyl-5-phenyl- [1,2,4] -azol-3-ylmethanone-sulfonyl-ethyl, 5-CF3-1-CHS- [1 ^. lyriazol-5-ylmethanesulfonylmethyl, 1-CH3-5-phenyl- [1,2,4] triazol-3-yl thanesulfonylmethyl, 5-CH 3 -1-phenyl- [1.2.4] iriazol-3-ylmethanesulfonylmethyl, 3-CH 3 - [1,2,4] oxadiazole-5-methanesulfonylmethyl, 3-CF 3 - [1,2,4] ] oxadiazol-5-yl-ethanesulfonylmethyl-1-phenyl-1H-oxadiazol-5-ylmethanesulfonylmethyl, 5-CH3 [1,2,4] oxadiazol-3-ylmethanesulfonylmethyl, 5-CF3- [1,2,4] oxadiazole - 3-ylmethanesulfonylmethyl, 5-phenyl- [1,2,4] oxadiazole-3-methanesulfonylmethyl, 2-CH 3 - [1,3,4] oxadiazol-5-ylmethanesulfonylmethyl, 2-CF 3 - [1,3,4] oxadiazol-54-methanesulfonylmethyl-2-phenyl- [1,3,4] oxadiazol-5-yl-ethanesulfonylmethyl, 3-CH3- [1,2,4] iiadiazol-5-ylmethanesulfonylmethyl, S-CF1-Fluoro-thiazol-5-ylmethanesulfonylmethyl, 3- Phenyl- [1, 4-thiadiazol-5-ylmethanesulfonylmethyl] -S-CHa-fl, 2,4] thiadiazol-5-ylsulfonylmethyl, 5-CF3- [1,2,4] thiadiazol-3-methanesulfonylmethyl, 5-phenyl- [1,2,4] Thiadiazol-3-ylmethanesulfonylmethyl, 2-CH3- [1,3,4] iiadiazol-5-ylmethanesulfonylmethyl, 2-CF3- [1,3,4] thiadiazol-5-ylmethanesulfonate nylmethyl, 2-phenyl- [1,3,4] iiadiazol-5-ylmethanesulfonylmethyl, 2,2-difluoropyrrolidinylmethanesulfonylmethyl, 3,3-difluoropyrrolidinylmethanesulfonylmethyl, 3-CF3-N-CH3-pyrrol-2-ylmethanesulfonylmethyl-ring, 3-CN-N -CH3-pyrrol-2-ylmethanesulfonylmethyl, 4-CF3-N-CH3-pyrol-2-ylmethanesulfonylmethyl, 4- (1-CH3-1-hydroxyethyl) -N-CH3-pyrrol-2-ylmethanesulfonylmethyl, 1,3-dimethylpyrrole -2-ylmethanesulfonylmethyl, 4-CF3-N-CH3-pyrrol-3-ylmethanesulfonylmethylgmpa, 4-CN-N-CH3-pyrrol-3-ylmethanesulfonylmethyl, 4-CN-N- (3J3,3-trifluoropropyl) pyrrole-3 -ylmethanesulfonylmethyl-2-CF3-N-CH3-pyrrole-3-ylmethanesulfonylmethylamino, 2-CF3-N-phenyl-pyrrol-3-ylmethanesulfonylmethyl, 4-CF3-pyrrol-2-methanesulfonylmethyl, 4- (1-CH3-1-hydroxyhexyl) ) Pyrrol-2-ylmethanesulfonylmethyl, 27 27 LV 13669 3-CH3-pyrrol-2-ylmethanesulfonylmethyl, 4-CF3-pyrrol-3-ylmethanesulfonylmethyl, 2-CF3-pyrrole-2-ylmethanesulfonylmethyl, 3-CF3-pyrrole-2 - ilmethanesulfonylmeyl, 2-CF3-pyrrole-4-ylmethyl n-sulfonylmethylgmpa, 2-CF3-N-CH3-pyrrol-4-ylmethanesulfonylmethyl, 3-CF3-fur-2H-methanesulfonylmethyl, 3-CN-fur-2-ylmethanesulfonylmethyl, 3-CF3-fur-4-ylmethanesulfonylmethyl-ring, 3- CN-fur'4-ylmethanesulfonylmethyl, 2-CF3-fur-3-ylmethanesulfonylmethyl, 3'CF3-thiazol-2-ylmethanesulfonylmethyl, 3-CN-thiazol-2-ylmethanesulfonylmethyl; 3-CF 3 -thiazol-4-ylmethanesulfonylmethyl, 3-CN-thiazol-4-ylmethanesulfonylmethyl, 2-CF 3 -thiazol-3-methanesulfonylmethyl, N-CF 13 -3-CF 3 -1H-pyrazol-5-ylmethanesulfonylmethyl, N-CH 3 - 3- (1-CH3-1-Hydroxyethyl) -1H-pyrazol-5-ylmethanesulfonylmethyl, N-CH3-3-phenyl-1H-pyrazol-5-ylmethanesulfonylmethyl, N-CH3-3-CF3-1H-pyrazof- 4-ylmethanesulfonylmethyl, N-CH3-4-CN-1H-pyrazol-3-ylmethanesulfonylmethyl, N-phenyl-4-CN-1H-pyrazol-3-ylmethanesulfonylmethyl, N-phenyl-3-CF3-1 H -pyrazol-4-one 1-methanesulfonylmethyl, N-febii-5-CF3-1H-pyrazole-34lmethanesulfonylmethyl, (N-CF) 3-4-CF3-1H-imidazol-2-ylmethanesulfonylmethyl, [N-CH3-4- ( 1-CH3-1-Hydroxyethyl) -1H-imidazol-2-ylmethanesulfonylmethyl, (N-CH3-4-phenyl-1H-imidazol-2-ylmethane) sulfonylmethyl-1-N-CH3-3-CF3-1H-pyrazole- 4-Methanesulfonylmethylgmpa, (N-CH3-2-CF3-1H-imidazol-5-methanesulfonylmethyl (N-CH3-2-phenyl-1 H -imidazol-5-ylmethan) sulfonylmethyl, (N-CH3-5-CF3) 1 H -imidazol-4-ylmethan) sulfonyl ethyl (N-phenyl-5-CF3-1H-imidazol-5-ylmethan) sulfonylmethyl, 4-CN- [1,2] oxazol-5-methanesulfonylmethyl, 4-CN-3-phenyl [1,2] oxazole -5-methanesulfonylmethyl, 4-CN- [1,2] oxazol-3-ylmethanesulfonyl [methyl, 4-CN-5-phenyl- [1,2] oxazol-3-yl] -methanesulfonylmethyl-4-CN-isothiazol-5-yl 4-CN-isothiazol-5-ylmethanesulfonylmethyl, 4-CN-5-phenyl-isothiazol-3-ylmethanesulfonylmethyl, 4-CF3- [1,2] oxazole, 4-CF3- [1,2] oxazole -5-ylmethanesulfonylmethyl, 4-CF 3 -3-CH 3 - [1,2] oxazol-5-ylmethanesulfonylmethyl, 4-CF 3 -3-phenyl- [1,2] oxazol-5-ylmethanesulfonylmethyl, 4-CF 3 - [1,2] oxazol-3-ylmethanesulfonyl-ethyl, 4-CF3-5-CH3- [1,2] oxazol-3-methanesulfonylmethyl, 4-CF3-5-phenyl- [1,2] oxazol-3-ylmethanesulfonylmethyl, 3 - CF3- [1,2] oxazol-4-ylmethanesulfonylmethyl, 5-CF3- [1,2] oxazol-4-ylmethanesulfonylmethyl, 4-CF3- [1,2] oxazol-3-ylmethanesulfonylmethyl, 4-CF3-3- CFI3- [1,2] oxazol-5-ylmethanesulfonylmethyl a, 4-CF3-3-phenyl- [1,2] oxazol-3-ylmethanesulfonylmethyl, 4-CF3- [1,2] oxazol-3-ylmethanesulfonylmethyl, 4-CFa-S-CH5-fl] ilmethanesulfonylmethyl, 4-CF3-5-phenyl- [1,2] oxazol-3-ylmethanesulfonylmethyl, 3-CF3- [1,2] oxazol-4-ylmethanesulfonylmethyl, 5-CF3- [1,2] oxazol-4-ylmethanesulfonylmethyl 4-CF 3 - [1,2] oxazol-5-ylmethanesulfonylmethyl, 4-CH 3 -3-phenyl- [1,2] oxazol-5-ylmethanesulfonylmethyl, 4-CH 3 - [1,2] oxazol-3-ylmethanesulfonylmethyl, 4-CH 5 -S-phenyl-1 H -hexazol-5-ylmethanesulfonylmethyl, 28 3 -CH 3 - [1- (4-hydroxymethyl) methyl] -5-CH 3 - [1,2] oxazol-4-ylmethanesulfonylmethyl, 4-CH 3 -isothiazol-5 -ylmethanesulfonylmethyl, 4-CH3-3-phenyl-isothiazo [-5-ylmethanesulfonylmethyl, 4-CH3-isothiazol-3-ylmethanesulfonyl-methyl] -amino, 4-CH3-5-phenyl-isothiazol-3-ylmethanesulfonylmethyl, 3-CH3-isothiazol-4-yl 5-CH 3 -isothiazol-4-ylmethanesulfonylmethyl, 4-CF 3 -2-CH 3 - [1,3] oxazol-5-ylmethanesulfonylmethyl, 4-CF 3 - [1,3] oxazole ilmethanesulfonylmethyl, 4-CF3-phenyl- [1,3] oxazol-5-ylmethanesulfonylmethyl, 5-CF3-2-CH3- [1,3-oxazol-4-ylmethanesulfonylmethyl, 5-CF3- [1,3] oxazol-4-ylmethanesulfonylmethyl] , 5-CF3-2-Phenyl- [1,3] oxazol-4-ylmethanesulfonylmethyl, 5-CH3- [1,3] oxazol-2-ylmethanesulfonylmethyl, 5-CFs-fl.Soxazol-4-methanesulfonylmethyl, 5-phenyl- [1,3] oxazol-2-ylmethanesulfonylmethyl, 4-CH 3 - [1,3] oxazol-2-ylmethanesulfonylmethyl, 4-CF 3 - [1,3] oxazol-4-ylmethanesulfonylmethyl, 4-phenyl- [1,3] oxazole- 2-ylidenhanesulfonylmethyl, N-methylindol-2-ylmethanesulfonylmethyl, 3-CF3-indol-2-ylmethanesulfonylmethyl, 3-CF3-N-methylindol-2-ylmethanesulfonylmethyl, 5-fluoro-N-methylindol-2-ylmethanesulfonylmethyl , N-Methylindol-3-ylmethanesulfonylmethyl-J-ring, 2-CF3-indol-3-ylmethanesulfonylmethyl, 2-CF3-N-methylindol-3-ylmethanesulfonylmethyl, 5-fluoro-N-methylindol-3-ylmethanesulfonylmethyl, 5-CF3 -N-methylindol-4-ylmethanesulfonylmethyl, 5-CN-N-mstylindol-4-ylidene Phenylimidyl, 2-CF3-N-methylindol-4-ylmethanesulfonylmethyl, 3-CF3-N-methylindol-4-ylmethanesulfonylmeyl, 6-CF3-N-methylindol-7-ylmethanesulfonylmethyl, 6-CN-N- methylindol-7-ylmethanesulfonylmethyl, 2-CF3-N-methylindol-7-ylmethanesulfonylmethyl, 3-CF3-N-methylindoF7-methanesulfonylmethyl, benzofuran-2-ylmethanesulfonylmethyl, 3-CF3-benzofuran-2-ylmethanesulfonylmethyl, 3 - CN-benzofuran-2-ylmethanesulfonylmethyl, 5-F-benzofuran-2-methanesulfonylmethyl, benzofuran-3-methanesulfonylmethyl, 2-CF3-benzofuran-3-ylmethanesulfonylmethyl, 2-CH3-benzofuran-3-ylmethanesulfonylmethyl, 5-F- benzofuran-3-ylmethanesulfonylmethyl, 5-CF3-benzofuran-4-ylmethanesulfonylmethyl, 5-CN-benzofuran-4-ylmethanesulfonylmethyl, 2-CF3-benzofuran-4-ylmethanesulfonylmethyl, 3-CF3-benzofuran-4- ylmethanesulfonylmethyl, 6- CF 3 -benzofuran-7-ylmethanesulfonylmethyl, 6-CN-benzofuran-7-ylphenenesulfonylmethyl, 2-CF 3 -benzofuran-7-ylmethanesulfon phonylmethyl, 3-CF 3 -benzofuran-7-ylmethanesulfonylmethyl, benzothen-2-ylmethanesulfonylmeyl, (3 -CF 3-benzothen-2-ylmethane) suffonylmethyl, 29 29 LV 13669 (S-CN-benzothen-1-ylmethanesulfonylmethyl, (5-F) benzothen-2-ylmethane) sulfonylmethyl, benzothen-3-ylmethanesulfonylmethyl, (2-CF3-benzoten-3-ylmethane) sulfonylmethyl, (2-CH3-benzothen-3-ylmethane) sulfonylmethyl, (5-fluorobenzothen-3-ylmethan) sulfones methyl, (5-CF3-benzothen-4-ylmethane) suffonyl methyl, (5-CN-benzothen-4-ylmethane) sulfonylmethyl, (2-CF3-benzothen-4-ylamine) sulfonylmethyl, (3-CF3) benzothen-4-ylmethane) sulfonylmethyl, (6-CF3-benzophen-7-ylmethane) sulfonylmethyl, (6-CN-benzothen-7-ylmethane) su (phonylmethyl, (2-CF3-benzothen-7-ylmethane)) sulfonylmethyl, (3-CF3-benzothiol-74lmethane) sulfonylmethyl, N-methylbenzimidazol-2-ylmethylsulfonylmethyl, (5-fluoro-N-methyl [benzimidazol-2-ylmethanone [phenylmethyl, (N-methylindazol-3-ylmethane) sulfonylmethyl] , (5-Fluoro-N-methylindazol-3-ylmethane) sulfonylmethyl, (2-CF3-N-methylbenzimidazol-4-ylmethan) sulfonylmethyl, (2-CF3-N-methylbenzimidazol-7-ylmethan) sulfonylmethyl [ , (N-methylindazol-4-ylmethan) sulfon [methyl, (5-CF3-N-methylindazol-4-ylmethane) sulfonylmeyl, (3-CF3-N-methylindazol-4-ylmethane) sulfonylmethyl, (6- CF3- N-methylindazol-7-ylmethyl) with [methylmethyl, (6-CN-N-methylindazol-7-ylmethane) sulfonylmethyl or (3-CF3-N-methylindazol-7-ylmethane) sLi! meiyl.

In the above-mentioned groups, the stereochemistry at the carbon to which R5 is attached is (R) and to which R4 and R6 are attached (S).

In the above-mentioned groups, the stereochemistry at the carbon to which R 0 and R 6 are attached is (R) and to which R 4 is (S).

(B) A preferred group of other compounds of formula (I) is wherein: R 3 is alkyl, preferably methyl or ethyl, and R 4 is alkyl, preferably methyl, ethyl, propyl or buty, and more preferably R 4 .and methyl. Preferably R3 and R4 are methyl.

(C) Another preferred group of compounds of formula (I) wherein R3 and R4 together with the carbon atom to which they are attached form cycloalkylene, preferably cyclopropylene, cyclopentylene or cyclohexylene, more preferably cyclopropylene. .

[0116] (D)) Oh! one group of compounds of formula (I) which is preferred is where R 3 and R 4 together with the carbon atom to which they are attached form a piperidin-4-yl group substituted at the nitrogen atom with an ethyl group of 2.2; , 2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, or 1,1-dioxotetrahydrothiopyrene [0117] (E) A further preferred group of compounds of formula (!) Is where R 8 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl, and R 7 and R 8 are hydrogen. (F) Another preferred group of compounds of formula (I) wherein R6 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2 - pentafluoroethyl, and R8 is hydrogen.

(G) Another preferred group of compounds of formula (I) wherein R6 is haloalkyl, preferably difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl or 1,1,2,2,2- pentafluoroethyl, R7 is alkyl, preferably methyl, ethyl or propyl, and R8 is hydrogen.

(H) Another preferred group of compounds of formula (I) wherein R6 is haloalkyl, preferably 1,1,2,2,2-pentafluoroethyl or 1,1,2,2,3, 3,3-Heptafluoropropyl, R7 and R8 are hydrogen.

Preferred groups of groups (B) - (H) to be preferred include those wherein R 1, R 2, R 0, R 6, R 7 and R 8 are as previously defined for (A) .

Preferred groups of groups (D) - (H) to be preferred include those wherein R 1, R 2, R 3, R 4 and R 0 are as previously defined for group (A).

It should be emphasized that references to the above-mentioned embodiments of the invention for which preference is given include all combinations of individual groups and groups which are preferred unless otherwise specified.

[0124] The most common compound of the formula (I) wherein R1 is hydrogen, R6 is trifluoromethyl and the other groups according to Table 1 below are as follows:

fa ga H5 0

yWJ 0 R3 R * ll 13669

'J 4-F-phenyl-4-F-phenyl-4-F-phenyl-4-F-phenyl-4-F-phenyl-phenyl-4-phenyl-phenyl-4-phenyl-1-phenyl-4-phenyl-1-carboxylic acid A S0 .0 cm ώ 1 cd A g ^ DO Y 1 1 cd A Ξ ^ 0 ′ s 1 n- cd A 60 ^ 60 · A 9 p · cd A g 3P • r— (PJJ (i is 1 4-F-Phenylgroup 4-F-Phenyl 1 Ή, 0 A fi =? As cn 60 4-F-phenylmg 4 (-H 1 - i h - < 1 < K f I 1-1- (cf.MM W o W w k a cd A Eb »'0 r- | co £ 3 ICd OS ΓΛ O p O' o Cd a 2 ω AO g ρ £ co icd 0 r- ' 1 m d cd A 60 1 3 (—1 1 P CO icd 03 s 'd' o cd ρ ω og '5 c§ co p icd o' po po d d d d M M M M M M M M ip 0 i— · j = C1 p n_ O 3 o cd A p 5b l 0 g | 0 to! g < - > o " o- _o 3 'o cd ptp jy 0' P cS co ičd 0 p cn 1 C- Ό o, cd r 0 ή -g • § X X) g ′ 3 3 * p co i 9 9 r • d r d d 0 d CO d d ω ω gr 0 0 * 0 CO i dd 0 pppp | 3 3 'o cd ο p Eb 0 fc co icd 0' (* > p g _o 3 0 cd A g _6p 0 «s CO i5 0 cn 1 C Ό A cd A p " · * —l 0 r * 1 C 0 mc pi 'pi cd A ω »0 M 1 P co i5 0 p p > _, p 5. 3' 0 cd A p 5b 0 g | co s 0 9 A p AV * 0 cd pp Ol) {0 | α α 0 g A p A O o cd A p jx ° 0 s | 0 co p Ip 3 p cn p 3 n PA g 3 ° 0 (- · cd cs co icd 0 1 CN M Ό Mi Cd p 0 1 0 cn d & 3 ߧ a 0 m kCu 9 B Ν ' A Pi rr · * 10 rt p ^ B * Ο n 2 p * 0 co 1 10 ri & cd OS y 60 f υ rn wu rn u cd ri 9 3P 0 Λ n 3 Γ & Ρ 0 K u P4 cd ps jsp n | OA 0 Cw AS 60 'a P a 0 cd pg Jap' a »- < pt i-hr H 1 cu A g 0 cd p, gr ^ P 0 cd α g 0 cd ot g JaO 0 ro un I— (U pO p4 K Jp i - -1 u) -p 1 - 4 hU MJ VU W u rn K um Τ 'u ro U u u u u H-4 1 — Γ w KV __ & aou A tti 3 a ^ s * o 60 1 - t 'a O Vt § · & u u u u a & nb   & 3 BO OD ' O 60 A & M Λ cd 3 & 3 0 60 Λ o Ut P < cd 3 & nd h O 60 1 'S, OM fg. 3 s 0 60 & O u cd 3 p rs s O 60 1 CO y > 0 'g cd ^ g' 5 60 cd   0 cd g ^ 60 'n 0 1-0 1 A p cd 3 «o 60 cd AC There were 3 0 0 iD Cu A g 00 3 0 0 A cd 0 60 3 p 0 rO A p cd 0 α.-Ab 0 60 1 'a O u A cd 3 A τί 5 O 60 1 * M A O M A nj 3 A ^ hn O 60 Stereochemistry at * C, ** C, *** C < z iZ Eo1 of tiο fti Ψ * q £ * ί ί r Jr * e ^ r Co * v ^. E? ttf • niο ni ξο 4 Vi 4r ψ • 4r Co " To * to * F * · * V— * £ 1¾ & cho " of s £ F 4 to 1 - 4 cn 1 - (VD 'Γ' H DO >—( (~ (N n n n ΐ ΐ £ £ £ 3 3 3 & & ..

4-F-Phenyl-4-F-phenyl-4-F-phenyl group rt Pvg, 0? 4 -1,34 2,4-di-F-phenylgroup 2,4-di-F-phenyl 2,4-di- F-phenyl-2,4-di-F-phenylgnjp. ^ 3 § * fi bfi 4 3 of 31 2,4-di-F-phenylmg rt α g tp 1 3 3 4-F-phenyl rt g Ofl * wp «t0 ¢ -1-4 1 Py4 Τ 'VH 4 -F-phenyl-4-F-phenyl-4-F-phenyl | 4-F-Phenyl-xi W f-j-r-4 T v-L-c is K 1 -H pn s a a rt Ο, must be 0 £, ο co ρ Iti 0! Q&A 3 rs CL r3 dO 0 ri r i r ω 3 1 " p CN rt Cl P 3) " o δ to irt 3 3 '3 1 CN rt ΕΓ bh a < - * 1 p cp-p 1! 'jg 0 r-ι I cd pd 2 0 1 1 CO p 5 0? 2 co P T 'i' 3 rt α p 3i 0 £ | co ira 0 g 3 1 3 o pyrid-3-ylmethanesulfonylmethyl cd p t 2 tp 0 2 | co irt 0 t-1 CO p " ΰ p t 1-oxopyridin-3-yl-ethanesulfonylmethyl ring cd p o0 0 co -2 .3 'g Ό 4-4' 3 ^ k. 52 o iS CO c_i ^ 0 g i-1 · F l rt α gb ο §3 | 1 rp rt 1 ^ "q gi" · t .3 OOP co v · n, 55 CN SW- 3 ο rt pt 1 l— * < 3 OT pp 0 2 3 ρ '3 ri p ah 0 g | co irt 0 rd, p o ir '0 3 cd p ^ 3 0 1 11 0 s 00 0 T td 1— (--4 U' 3 3 3 1 1—4 y 4 goi? n d t > ~ ϋ d ^ -F • -4 0 O 0 ^ -P ^ OT 3 0 rt g bfl - 4 0 g 1 3 co 1 d 00 Γ-Ί α CO n, p 3 Cd 0 r ^ ~ ppo cb 1 Oi O * s, 3 p 6 3 > 1 pp R ^ O rv ypo 3 rt pp 3 p p (jO p / op 3 rt 3 ^ go bQ 1 p, p o p i o p p 0 0 s. Ξ δ bo ethyl group ro hf-t H HH i-t O • M o 3 < u rt g 3? 0 r L) r * l r P P r 0 0-1! K uw 10 0 v < P4 cd 3 a ^ e 0 ttO τ 'H OU τ' u R f 'R 0' 3 0 u R Cu R a 0 W3 1 1 UR R J2 R ^ g 0 M 3 p R 1: 3 la 0 oc 1 '3 0 R Cd - RM g O OJD' 3 0 j- · P4 0 0 1 '3 q. R ^ o 0- 3 g O bO 1' 3 O 1 - i R & 3 < 3 B o d 3 'R < 3 > 3 < 3 > 1 < 3 > 3 ° C 3 ° C R 3 O 2 1 '3 p 3 ° r 1 2' 1 '3 p R * cc 3 ^ 2 O OD' 3 O R1 03 3 ^% 2Ί o & 0 * 3 p P * cd 3 a ^ go bO 3 p '3 ca 5 & 25 co O bO 'ftf ξο 5i * Jr co " 5i * g?: Td R > Jp * - Co F) r F v_F to v_- F -5r g * to' 4r * ci 4 ε ?. ? 5? t? p * Ψ rp. F 3: · s? v_ ai ψ • Jr Co σΐ ό CN i-I CN CN CN CN CN CN CN CN CN CN CN CN CN CN co co CN CO m co. T co. in co vd CO LV 13669

4-F-Phenyl 4-F-phenylgnip cd A 3 v5P3, Oα1A i nt 4-F-phenyl-4-F-phenyl-4-F-phenylgmpa 4-F-phenyl-4-F-phenyl-4- F-Phenyl 1 4-F-phenyl cd A 3 rS3 &quot; SA 1 1¾ J cd AS CJ3, * * S, 0) &lt; 4-1 (4-F-phenyl 4-F) -phenylgroup 4-F-phenyl-3, 1-N-3-N-O-4-F-phenyl group &lt; t &gt; hM w K i-rC AKWW w h h · AA nd cd a H or 0 &lt; 2 τη iS 0 Ē, 0 cd A p 5b 0 r-j 1 to (p 0 pop os o o cS cd A &amp; 03 P 1 P k, - o 0 CO 0 ^ Ο Έ {, 0 Ν 'A cMopropylinetansulfonylmethyl-group cd A p feb' • 4 — I 0 t-i ft icd 4— &gt; 03 e-48 0 'o 1 CN Cd 1 03 3 1 to in 03 Pt - £ 0 i £ '5 1 CN I i &lt; i. N cd 0 pr' a cd 1 s Jl 0 0 ^ s 5 3 s S, p 'J5 N 1 1 &lt; ~ f' SP 0 A ' cd! 1 «- (4-1 0 0 ee fi 3 fi v S i 2 2 -chlorb enzyme biphenyl-4-ylsulfonylmethyl cd ot 2 ω 'uli 0 g OO 0 &gt; B 0 Gp 1 m 3 3-methylsulfonylbenzylsulfonylmethyl ca A p iāb 0 2 1 co c Έ 0 _g co p A _o 'o cd A g jd? »▼“ »0 3' 2« a 1 1 0 4— '1 N 1 i 4 0 s l2 1 ΐ to 1 ( * Section 3 p4 «S 00 1 | v d N &quot; fc £ 2-Cyclohexyl-ethylpyrimid-3-yl-ethylsulfonylmethyl-benzyloxymethyl-cyclopropylene glycol cd AP Jj) O HH A o Cyclobutylmethyl-gmp ro FH A u cd S 0 • -r Ht o cd α 3 0 cd Ph g oo 0 cd A 2 0 cd A g 00 1 Ή Ά 0 cd A g ^ 00 0 cd p £ 0 cd rv p 5o t — 4 0 cd A g 00 0 cd A 2 00 03 cd A 8 o ro wo K f K tr * A • τ 'AK tr &lt; The V-pt A s 'T1 A cd A S &amp; 0 w «n K υ K 1 Έ o M A cd 3 3 O O bD 1 -H' E. o A cd £ &amp; M g '5 ttO cildopropyl group A-1-I-9 o 3 g u Cyclopropyl group 1 1 p 3 &amp; 3 3 o W) Έ o l-i 51 p 2 λ α a b b Cyclopropylcyclopropyl-! 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cd (? PP? d? 4-F-phenyl-4-F-phenyl-4-F-phenyl-1-d '103-d' pp &quot; s cd p cd g? S? i? 4-F-phenyl 4-F-Phenyl group cd E) PP PP d cd P g 0 &amp; 'E P P 4 tetrahydropyran-4 long-chained 1-1 &gt; —- i P K-i H a K K E cd P 5 -' p f ~ l 1 cn 1 co rd &lt; § 1 co E &gt; G5? * 4 [alpha] C [alpha] C [alpha] - (t-butoxycarbonyl) piperidin-4-ylmethyl group cd P g δΰ F3 id (DP 0 1 CN cti P g ^ fcp r-1 cS CN od t &lt; + &gt; 1-methylsulfonylpiperidine-4 - Methylgmpa 1-Aminocarbonylpiperidin-4-ylmethyl-1-methylcyclopentylmethyl 1 -methyl] -cyclopentylmethylglycol, cos R c 3 V rd ethyl group cd P go cd P gu cd P t i cd P gj =? o cd P? 3 cd P? O cd P g Q0 O cd P o cd P g J3fl ϋ P HH JrC PKH Hp 1-1 'T1 P Hrl P i-p PP cyclopropylcyclopropyl- gmpa cyclopropyl group I 'pou Ρ cd ^ P sy c' p pp Ρ cd. S £ -S '3 cio cyclopropyl group P' pou d cd ^ Ρ ^ c &gt; & 0 P o MP cd r2 p 1¾ k U 00 pnazol-3- long group 'pp c cd, 2 p 4 5 * * 4 4 4 ī T · * 5 5 5 5 t &lt; L_ * lt L λ * ___ *, s ?-'Ϊ́ ^ — ^ — M M K-1 1 to to to M M M 1 1 1 1 1 1 1 l l co Li Li Li Li Li Li Li Li Li Li Li Li Li CT) VO o C-1c cn (NG d d &quot; vo CA 'O ΟΛ P) cn oo cn CO cd F-Qt E 5_ ow E in CO CO CO Λ Λ Λ CO Λ CO n CO CL CO CO oc CO 'CO ZS & 2 T3 CO o TO) TO o cd COE ω E 'o cω &gt; CO «oc

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The following describes the compounds of the invention. co Ph 4-F-phenyl-4-F-feuylgmpa 2,4-di-F-phenylgmpa cd k1 2 '3 i? 4 '3 N 2,4-di-F-, fen.ilgru.pa cd &lt; a ° Γ 2 3 4 '3 Γ ·, &lt; £ CN &lt; + - &lt; out 1-½ m a cd a g 4 4 4-i ļ ļ 1 1 1 ά co ļ ļ co r r r r r ά ά ά ά ά (((l l l l ά ά yes O ΓΟ 7 ^ | Ā 0 Pi Icd. - cd o_, yes 0 ΓΟ - 11 'cL 0 P i5 h «9 s« J * ΙΞ cd ο yes 0 i C • • 3 IK IK IK IK IK IK? O p 1 - '' C a cd n P yes 0 P | 00 ip 0 P CO ”a 0 1 g ΓΠ - - ^ &amp; Ā 0 His ira 81 òτ 22 cd n! its o. p-cd O 2 g Ό to 1 ιό; o O Is 2 g o co __tL 1-7 u m 'τ' i-r o H? u i§ p a cd rB a ^ ed it. pB. r- &gt; 1-4 1-½ U &gt; -P 1-½ u rn K rt [g J50 a O U. Dh o 3 o cd Oh g a a cd p c δ JaO ao J-, ao 3 o cd a O o o o o _ d d d d d g g)) o o o o o o o o ί ί 0 ί ί ί 0 ί 0 ί i-. ^ 0 · 0 5q 'a * * · * Co F * £ F co. # · F * Co-K-F * Co F 4r Co k. . »- &lt; CN co šf vo. vo · 39 39 EN 13669 GENERAL SYNTHESIS SCHEME.

[0126] The compounds described in the invention can be obtained by the techniques illustrated in the following reaction schemes.

Raw materials and reagents to be used to obtain these compounds may be purchased from commercial suppliers such as Aldrich Chemical Co., (Milvvaukee, Wis.), Bachem (Torrance, Calif.) Or Sigma (St. Louis, Mo.) or be prepared by techniques known to those skilled in the art according to the procedures described in Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemisiry (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes only illustrate some of the techniques that can be used to synthesize the compounds described in the present invention, and various modifications of these schemes are possible and can be used by those skilled in the art. who will refer to this invention.

[0128] The raw materials and reaction intermediates, if desired, can be separated and purified by conventional methods including, but not limited to, filtration, distillation, crystallization, chromatography and the like. These materials can be characterized by traditional methods, including physical constants and spectral information.

Unless otherwise stated, the reactions described herein will be carried out at atmospheric pressure in a temperature range of about -78 ° C to about 150 ° C, preferably from about 0 ° C to about 125 ° C, and more preferably at room (or ambient) temperature, e.g. ° C.

The reactions described below may require protection of reactive functional groups such as protecting groups such as hydroxyl groups, amino groups, imino groups, thiogroups, or carboxyl groups if the presence of a corresponding group in the final product is required to exclude the unwanted participation of these groups in the reactions. Traditional protecting groups can be used according to standard procedures, see, e.g., T.W.

Greene and P.G. M. Wuts in “Protective Groups and Organic Chemistn / &quot; John Wiley and Sons, 1999.

Compounds of formula (I) wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 8 are as defined in the Summary of the Invention and R 7 is hydrogen may be obtained by following the procedure described in Reaction Scheme 1 below. 1 scheme 40 40 Re Rs Ο .1 1 'f A AR ΗζΝ ^ Υ O 2 i-Vv ^ Ra N γ' a 0

Rs A / V? R1 o R5 5ν 4 ° R5 0 li 4 &gt; [0131] When the keion of formula 1 wherein R6 and R8 are as defined in the Summary of the Invention, reacts with an α-aminoester of formula 2, wherein R is a carboxyl protecting group, preferably an alkyl group, preferably a methyl group, and R5 is as defined in the Summary of the Invention. The reaction is carried out in the presence of a suitable dehydrator such as TiCl4, magnesium sulfate, isopropyl trifluoroacetate, in the presence of a base such as diisopropylethylamine, pyridine and the like, and in a suitable organic solvent such as mefylene chloride to give the imine. The imine is reduced with a suitable reducing agent such as sodium borohydride, sodium cyanoborohydride and the like, in a suitable organic solvent such as methanol, ethanol and the like.

[0132] Compounds of formula 1 such as 2,2,2-trifluoromethylacetophenone and 2,2,2,4-tetrafluoraceffencns are commercially available. Others can be obtained by techniques well known to those skilled in the art, the α-aminoesters of formula 2 can be obtained by techniques well known to those skilled in the art, such as the PCT application with publication no. WO 03075836; WO 00/55144; WO 01/19816; WO 02/20485; WO 03/029200; 60 / 422,337, U.S. Pat. 6,353,017B1, 6,492,662B1, 6,353,017 B1 and 6,525,036B1, 6,229,011B1, 6,610,700 - these inventions are incorporated herein by reference in their entirety.

[0133] The hydrolysis compound 3 of the ester group results in a compound of formula 4. The hydrolysis conditions depend on the type of protecting group. For example, when R is alkyl, hydrolysis is carried out under aqueous basic hydrolysis to give the corresponding acid of formula 4. Generally, the reaction is carried out with cesium carbonate, lithium hydroxide and the like in an aqueous solution of alcohol such as methanol, ethanol and the like.

[0134] The compound 4 then reacts with α-hydroxycetoamide of formula 5 to form a compound of Formula 6. Generally, the reaction is carried out in the presence of a suitable additive such as, for example, benzotriazol-1-yloxyrispyrrolidinophosphonium hexafluorophosphate (PyBOP®), O-benzotriazole-1. -yl-Ν, Ν, Ν ', N-tetramethyluronium hexafluorophosphate (HBTU), O- (7-Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluron hexafluorophosphate (HATU), 1- ( 3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDO) or 1,3-dicyclohexylcarbodiimide (DCC), optionally in the presence of 1-hydroxybenzotriazole (HOBT) and bases such as, / N-diisopropylethylamine, triethylamine, N-methylmorpholine and the like . Generally, the reaction is carried out at a temperature between 20 ° C and 30 ° C, preferably about 25 ° C, and the completion of the reaction takes from 2 to 24 hours. Suitable solvents for the reaction include inert organic solvents such as halogenated organic solvents (e.g. methylene chloride, chloroform and the like), acetonitrile, N-dimethylformamide, solvents belonging to the ether group such as tetrahydrofuran, dioxane and the like.

Alternatively, the above-mentioned flux step can be carried out by first converting the compound 4 into an active acid derivative such as succinimide ester, and then reacting this ester with α-hydroxycetoamide of Formula 5. The completion of the reaction usually takes from 2 to 3 hours. The conditions of this reaction depend on the type of active acid derivative. For example, if this derivative is the acid chloride of compound 4, then the reaction is carried out in the presence of a suitable base (e.g., using triethylamine, diisopropylethylamine, pyridine and the like). Suitable solvents for the reaction are polar organic solvents such as acetonitrile, N, N-dimethylformamide, dichloromethane or any suitable mixture of these solvents. Compounds of formula 5 can be prepared by methods well known to those skilled in the art, for example, these compounds can be obtained by the procedures described in PCT application no. WO 02/18369, the results of which are incorporated herein by reference in their entirety.

[0136] Oxidation of the hydroxyl group in compound 6 with a suitable oxidizing agent such as ΟΧΟΝΕ® yields a compound of formula (I).

Alternatively, compounds of formula (I) wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 8 are as defined in the Summary of the Invention and R 7 is hydrogen may be obtained by following the reaction scheme 2 below. Scheme 2 I £%% -J * 1 Re ψ Jv 'A &gt; R? ^? 8 S 16 R5 B rjB let _ x A, oh f? N w "* W h o .Gpe n

For a compound of formula 8 wherein R5 is as defined in the Summary of the Invention and PG is a suitable oxygen protecting group reacting with the hemiacetal of Formula 7, wherein R6 is as defined in the Summary of the Invention, an imine compound of Formula 9 is obtained by treating Compound 9 with a lithium organic compound with Formula R8Li, wherein R8 is not hydrogen, yields a compound of 10. Then removing the oxygen protecting group, oxidizing the resulting alcohol 11, results in a compound of formula 4 which is then converted to a compound of formula (I) as described in Scheme 1 above. Suitable oxygen protecting groups and reaction conditions in which these groups can be attached and removed are described by Greene, T. W .; and Wuts, P. G. M .; Protecting Grou ^ s in Organic Synthesis; John Wiley &amp; Sons, Inc. 1999 42

Alternatively, compounds of formula (I) wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 7 are as defined in the Summary of the Invention and R 8 is hydrogen may be obtained by following the reaction scheme 3 below. Scheme 3 0 0 Vf1 HO 'Λ

, OR

Rc RE BFs,% 0 R *

.0R

O Ϊ2 m For the amino acid compound of formula 2 wherein R is alkyl and R 5 is as defined in the Summary of the Invention by reacting with a hemiacetal compound of formula 7, compound 2- (1-hydroxy-2,2,2-trifluoroethylamino) acetate is obtained. The reaction is carried out in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, and in an aromatic hydrocarbon solvent such as toluene, benzene and the like.

Treatment of compound 12 with a compound of formula R6H wherein R7 is aryl or a heteroaryl group under the conditions of the Friedel-Crafts reaction or trialkylaluminium in toluene affords the compound of formula 3 which is then converted to the compound of formula (I) as described above.

Alternatively, compounds of formula (I) wherein R 1, R 2, R 3, R 4, R 5, R 6 and R 7 are as defined in the Summary of the Invention and R 8 is hydrogen can be obtained by following the reaction scheme 4 described below. 4th Scheme Fz Rz 1? 5 *? · * R ^ OTf 13 + t X sOR '0 14 1 1 neobiggers] t 1 - AV' - 15 15

, OH R6 'R? - "#Vtx" 5 17 sktiv &amp; is acid 4tvaslnJ] or precursor (I) 1 2 [0141] For a compound of formula 13, wherein R6 and R7 are as defined in the Summary of Invention 3, with a compound of formula 14 wherein R 'is hydrogen or a 4-carboxyl protecting group and Rz is R5 or a precursor group 5 (e.g., alkylene-S-trityl, -alkylene-S-alkylene-heteroaryl and the like) from 6 to R5 yields the compound of formula 15. The reaction is carried out with a suitable 7-tetrahydrofuran. , acetonitrile, benzene, toluene, xylene and the like, or mixtures of these solvents, and optionally in the presence of an organic or inorganic base. Preferably, the organic base is triethylamine, pyridine, N-methylmorpholine, 8 in an organic solvent including, but not limited to, diethyl ether, 43 43 LV 13669 colidine, diisopropylethylamine and the like. Better if the inorganic base is cesium carbonate, sodium carbonate, sodium bicarbonate and the like. Optionally, the reaction is carried out in the presence of a desiccant as a molecular sieve. The reaction is preferably carried out at room temperature.

[0142] Compounds of formula 13 can be obtained by methods well known to those skilled in the art. For example, a compound of formula 13 wherein R is phenyl or 4-fluorophenyl and R is trifluoromethyl may readily be obtained from commercially available 2,2,2-trifluoroacetophenone or 2,2,2,4'-tetrafluoroacetophenone, i.e. by reduction of the ketogroup to alcohol. using a suitable reducing agent such as sodium borohydride, lithium aluminum hydride and the like. The solvent used depends on the type of reducing agent. For example, if sodium borohydride is used, the reaction is carried out in the presence of an organic alcoholic solvent such as methanol, ethanol and the like. When lithium aluminum hydride is used, the reaction is carried out in an ethereal solvent such as tetrahydrofuran and the like. 2,2,2-Trifluoro-1-phenyl-ethanol or 2,2,2-trifluoro-1- (4-fluorophenyl) ethanol is reacted with triflic anhydride or trifluoromethanesulfonyl chloride to give the desired compound. Compounds of formula 13 wherein R7 and R8 are hydrogen and R6 is 1,1,2,2,2-pentafluoroethyl can be obtained from commercially available 2,2,3,3,3-pentafluoropropene-1-ol as described above. The optically enriched compounds of formula 15 can be obtained by reduction of the corresponding halogenated acetophenone with a suitable reducing agent such as catecholborane or BH3-DMS complex in the presence of a suitable catalyst such as (S) or (R) -oxazaborolidine or (S) or (/?). -a, α-diphenyl-2-pyrrolidinemethanol in the presence of BBN to give the hiral alcohol which is then converted into compound 13 as described above. Compounds of formula 14 are commercially available or can be obtained by techniques well known to those skilled in the art.

[0143] The carboxyl protecting group, except from the compound of formula 15, wherein R 'is a protecting group, yields a compound of formula 16. The conditions for removal of the carboxyl protecting group depend on the carboxyl protecting group type. For example, if R 'is alkyl, it is removed under basic hydrolysis using a base aqueous solution such as lithium hydroxide, sodium hydroxide and the like, and in an alcoholic solvent such as methanol, ethanol and the like. In addition, if the Rz group in compound 14 is a precursor group for R5, it can be converted to R5 before the ester is hydrolyzed to the stage or thereafter.

The compound 15 (where R 'is hydrogen) or the compound 16 is then converted to the activated acid derivative 17 (X is a cleavable group), which reacts with the aminoacetonitrile compound of formula 5 to give a compound of formula (I) when R 2 is R 5 or \ t precursor compound for compound (!) when Rz is a precursor group R5. The activated acid derivative can be prepared and then reacted with the compound 5 in a stepwise manner, or the activated acid derivative can be prepared in situ in the presence of compound 5. For example, if the activated acid derivative is an acid halide, then it is prepared by reacting the compound 16 with a halogenating compound such as thionyl chloride, oxalyl chloride and the like, and then reacting with the compound 5. Alternatively, the activated acid derivative is obtained from // 7, for the bond 16 and 5 44 in the presence of a suitable additive such as, for example, benzotriazM-iloxytispyrrolidinphosphonium hexafluorophosphate (PyBOP®), 0-benzotriazol-1-ene-β, Α / Λ / ram -tetramethyluronium hexafluorophosphate (HBTU), 0 - (7-Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) and like, in the presence of 1-hydroxybenzotriazole (HOBT) and in the presence of a base such as N, N-diisopropylethylamine, triethylamine, N-methylmorpholine and the like. Suitable organic solvents include inorganic organic solvents such as halogenated organic solvents (e.g., methylene chloride, chloroform and the like), acetonitrile, N-dimethylformamide, essential solvents such as tetrahydrofuran, dioxane and the like. When R 2 is a precursor group R 5, it is converted to R 5 to give a compound of formula (I), for example, by converting an -alkylene-S-alkylene-heteroaryl group into -α [alkylene-SO 2 -alkylene-heteroaryl under oxidation reaction conditions.

[0145] The compound of formula (I) can be converted into other compounds of formula (I). For example: A compound of formula (I) containing a hydroxyl group may be prepared except an alkyl / benzyl group of an alkoxy / benzyloxy substituent; if an acid group is present, hydrolysis of the ester group is performed; if cyano is present, the bromine atom is removed from the corresponding compounds of formula (I). The compound of formula (I) containing a cyano group can be converted into the corresponding carboxyl-containing compound by hydrolysis of the cyano group. Conversely, the carboxyl group can be converted into an ester group.

A compound of formula (I) can be obtained as a pharmaceutically acceptable acid addition salt by reacting the free form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable salt of a basic additive of formula (I) can be obtained by reacting the free acid form with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of the compound of formula (I) are mentioned in the Dinection section of this application. Alternatively, the mold forms of the compound of formula (I) may be prepared using raw materials as intermediate salts.

[0148] The free acidic or basic forms of the compounds of formula (I) can be prepared from the corresponding base additive salt or acid addition salt form. For example, the acid addition salt of the compound of formula (I) may be converted to the corresponding free basic form by treatment with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide and the like). The additive salt form of the compound of formula (I) may be converted into the corresponding free acid form by treatment with a suitable acid (e.g. hydrochloric acid, etc.).

[0149] The compound of formula (I) / V-oxides can be obtained by techniques known to those of ordinary skill in the art. For example, N-oxides can be obtained by treating a non-oxidised form of the compound of formula (I) with an oxidizing compound (e.g., trifluoroacetic acid, permaleic acid, 45 45 LV 13669 perbenzolic acid, peracetic acid, mepha-chloro-hydroxybenzoic acid and the like) in a suitable inert organic solvent (e.g. halogenated hydrocarbon such as dichloromethane at about 0 ° C. Alternatively, the N-oxides of the compound of formula (I) may be prepared from a suitable source of N-oxide.

The non-oxidized form of the compounds of formula (I) can be obtained from a compound of formula (I) / V-oxides by treatment with a reducing agent (e.g. sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride and the like) at a suitable inert organic solvent (e.g., acetonitrile, ethanol, dioxane water, and the like) at. 0 ° C to 80 ° C.

[0151] Prodrug derivatives of formula (!) Can be obtained by techniques known to those of ordinary skill in the art (e.g., Saulnier et al. (1994), Bioorganic and Medical Chemistry Letters, Vol. 4, p. 1985). For example, suitable blanks can be prepared by subjecting the non-derived compound of formula (I) to a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonyl chloride, para-nitrophenylcarbonate and the like).

[0152] The protected compounds of formula (I) can be obtained by techniques known to those of ordinary skill in the art. A detailed overview of techniques for preparing and removing protective groups is provided by T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley &amp; Sons, Inc. 1999

[0153] The compounds described in this invention can conveniently be prepared or produced as solvates (e.g., hydrates) as a result of the invention. The hydrates of the compounds described in this invention can be conveniently prepared by recrystallization from a water / organic solvent mixture using organic solvents such as dioxin, tetrahydrofuran or methanol.

[0154] Compounds of formula (I) can be prepared as individual stereoisomers of these compounds by subjecting the racemic mixture of these compounds to an optically active separation agent to form a diastereoisomeric pair, separating from the diastereomers and reducing the optically pure enantiomer. Although separation of enantiomers can be accomplished using covalent diastereoisomers of compounds of formula (I), dissociable complexes (e.g., crystalline diastereoisomeric salts) are preferred. Diastereoisomers have distinct physical properties (eg melting point, boiling point, solubility, reaction capability, etc.) and can be easily separated by differences in these properties. The diastereomer can be separated by chromatography or, preferably, by separation / splitting methods based on the solubility difference. The optically pure enantiomer is then regenerated together with the separating agent using any suitable techniques that "exclude racemization. For a more detailed overview of the methods that could be used to obtain stereoisomers of compounds from the racemic mixture of these compounds, see Jean Jacques Andre Collet, Samuel H. VVilen.

Enantiomers, Racemates and Resolutions, John Wiley &amp; Sons, Inc. (1981). 46

Preparation of Biological Preparations [0155] In practice, a number of biological preparation and purification processes can be used in the practice of this invention. Techniques for preparing organic preparations are well known in the art, as described below. [0156] Monoclonal antibodies can be obtained using standard techniques well known in the art, such as the method described in Kohlerand Milstein, Nature 1975, 256: 495 or modification of this technique, as well as the technique described in Bucketal. 1982, Irt Vitro 18: 377. Usually, the mouse or rat is immunized with MenB PS derivative with the protein carrier, killed and spleen (and optionally several large lymph nodes) removed and divided into separate cells. If desired, the spleen cells can be screened (after separation of non-specific adherent cells) by applying a cell suspension on a plate or hollow coated with an antigen. B-cells that express antigen-specific membrane-bound immunoglobulin will bind to the plaque and will not be rinsed off with suspension residues. The resulting B-cells or all the split spleen cells then merge with myeloma cells to form hydridomas. Typical lines of myeloma for hydridation include lines available in the American Type Culture Collection (ATCC).

Himeric antibodies consisting of human and non-human amino acid sequences can be derived from mouse monoclonal antibody molecules, reducing their immunogenicity in humans (Vinteretal Nature 1991 349: 293; Lobugiioetal.

Proc. Nat. Acad. ScL USA 1939, 86: 4220: Shaw et al. J. Immunol. 1987 138: 4534; and Brown et al Cancer Res. 198747: 3577; Riechmann et al. Nature 1988 332: 323; Verboeyen et al. Science 1988 239: 1534; and Jones et al.

Nature 1986 321: 522; EP with Publication No. 519, 596, published December 23, 1992; and U.K. patent with publication no. GB 2,276,169, published September 21, 1994).

[0158] Fragments of the antibody molecule, such as F (ab ') 2, FV, and sFv molecules capable of displaying monoclonal parent antibody molecules. Immunological binding properties can be obtained using known techniques: Inbaretal. Proc. Nat. Acad. Sd. USA 1972 69: 2659; Hochman etal Biochem. 1976, 15: 2706; Ehrlich et al Biochem. 1980 19: 4091; Huston et al. Proc. Nat. Acad. Sd. USA 1988 85 (16): 5879, · and U.S. Pat. 5,091,513 and 5,132,405, and U.S. Pat. 4,946,778.

Alternatively, the phage display system can be used to increase the monoclonal antibody molecule populations in vitro. Saiki et al. Nature 1986 324: 163; Scharf et al Science 1986 233: 1076; U.S. Pat. 4,683,195 and 4,683,202; Yang et al. J. Mol. Biol 1995 254: 392; Barbas, Methods: Comp. Meth Enzymol 1995 8:94; Barbas, etal. Proc. Nati. Acad.

Sd. USA 1991 88: 7978 ..

Coding sequences for heavy and light parts of Fab molecular chains selected from the phage display library can be isolated or synthesized and cloned into any other suitable vector or replica suitable for expression. Any expression system, including, for example, bacterial, yeast, insect, amphibious and mammalian systems can be used. The expression systems of bacterial origin 47 47 LV 13669 contain systems described in Chang et al Nature 1978 275: 615, GoeddeJetal. Nature 1979281: 544, Goeddeleta, NucleicAcids Res. 1980 8: 4057, European application no. EP 36,776, U.S. Pat. 4,551,433, deBoer et al. Proc. Nati. Acad. ScL USA 1983 80: 21-25, and Siebenlist et al., 198020: 269.

Yeast expression systems contain systems described by Hinnen etal Proc. Nati Acad. ScL USA 1978 75: 1929, Ito et al. Bacteriol 1983 153: 163, Kurtz et al Mol. Great. Biol 1986 6: 142, Kunze et al. J. Basic Microbiol. 198525: 141, Gleeson et al. J. Gen. Mlcroblol 1986 132: 3459, Roggenkamp et al. Mol. Gen. Genet. 1986202: 302, Dasetal J. Bacteriol. 1984, 158: 1165, De Louvencourt et al., J. Bacteriol. 1983 154: 737, Vanden Berg et al. Bio / Technology 1990 8: 135, Kunze et al. J. Basic Microbiol. 198525: 141, Cregg et al. Mol. Great. Biol. 1985 5: 3376, U.S. Pat. 4,837,148 and 4,929,555, Beach etal. Nature 1981 300: 706, Davidow et al. Curr. Genet. 1985 10: 380, Gaillard et al. Genet. 1985 10:49, Ballance et al Biochem. Blophys. Res. Commun. 1983 112: 284-289, Tilburn et al. Gene 1983 26: 205-221, Yelton et al. Proc. Nati. Acad. Sd. USA 1984 81: 1470-1474, KellyetalEMBOJ. 19854: 475479; European application no. EP 244,234 and International Publication no. WO 91/00357.

The expression of heterologous genes in insects can be achieved as described in U.S. Pat. 4,745,051, European applications no. EP 127,839 and EP 155,476, VIak et al. J. Gen. Virol. 1988 69: 765-776, Miller et al Ann. Rev. Microbiol. 198842: 177, Carbonell et al. Gene 1988 73: 409, Maeda et al. Nature 1985 315: 592-594, Lebacq-Verheyden et al. Mol. Great. Biol. 1988 8: 3129, Smith et al. Proc. Nati. Acad. Sd. USA 1985 82: 8404, Miyajima etal Gene 198758: 273, and Martin et al DNA 7:99. Several baculovirus strains and variants and the respective recommended host host cells are described in Luckow et al. Bio / Technology 1988 6: 47-55, Miller et al., GENETIC ENGINEERING, Setlow, J.K. et al eds., Vol. 8, Plenum Publlshing, p. 1986277-279, and Maeda etal Nature 1985315: 592-594.

The expression of mammalian expression can be achieved as described in Dijkema et al. EMBO J. 1985 4: 761, Gorman et al Proc. Nati. Acad. Sd. USA 1982 79: 6777, Boshartetal Keli 1985 41: 521, and U.S. Pat. 4,399,216. Other peculiarities of mammalian expression may be achieved as described by Ham et al Meth. Enz. 1979 58:44, Barnes et al. Biochem. 1980 102: 255, U.S. Pat. 4,767,704, 4,657,866, 4,927,762, 4,560,655 an re-issued US patent

No. RE 30,985, and International Publication Nos. WO 90/103430, WO 87/00195. .

The production of recombinant adenoviral vectors is described in U.S. Pat. 6,485,958.

The botulinum toxin type A can be obtained by administering and cultivating Clostridium botulinum cultures in an enzyme and collecting and purifying the mixture according to known procedures after fermentation. [0166] Any of the foregoing protein production techniques can be used to obtain a biological preparation that may be useful in the context of the present invention.

Pharmacology and Applicability The compounds described in the invention are selective inhibitors of cysteine proteases such as cathepsin S, K, B and / or F, and in particular cathepsin S, and are therefore useful in the treatment of diseases in which cysteine protease activity plays a role in disease pathology. and / or symptomatology. For example, the compounds described in the invention are useful in the treatment of autoimmune disorders including, but not limited to, the onset of diabetes in adolescents, psoriasis, scattered sclerosis, pemphigus vulgaris, Grapefruit disease, myasthenia ditch, systemic lupus erythematosus, rheumatoid arthritis and Flusimoto iriditis, allergic disorders. including, but not limited to, asthma, allogeneic immune responses, including but not limited to, organ transplants or tissue transplants and endometriosis.

Cathepsin S is also involved in disorders associated with excessive elastolysis such as chronic obstructive pulmonary disease (eg, emphysema), bronchitis, excessive respiratory elastolysis in asthma, and bronchitis, pneumonitis, and cardiovascular disease such as plaque hernia and atherosclerosis. . Cathepsin S is involved in the formation of fibrils and therefore inhibitors of cathepsin S are useful in the treatment of systemic amyloidosis. The efficacy of cysteine protease inhibitors of formula (I) can be determined by techniques known to those of ordinary skill in the art. In vitro experiments suitable for the measurement of protease activity and for the detection of protease inhibition by test compounds are known. Typically, the experiment will measure the hydrolysis of the substrate to the peptide base caused by the protease. A detailed review of experiments on the measurement of protease inhibition activity in Biological Examples 1-5, infra.

Uses and Pharmaceutical Compositions Compounds of formula (I) are generally administered by administering a therapeutically effective amount of any of the conventional and acceptable forms known in the art, and administering these compounds alone or in combination with one or more therapeutic agents. A therapeutically effective amount could vary widely depending on the severity of the condition, the age and health of the patient, the potential of the compound to be used, and other factors.

For example, therapeutically effective amounts of a compound of formula (I) may range from 10 micrograms per kilogram body weight (pg / kg) per day to about 100 milligrams per kilogram body weight (mg / kg) per day, usually about. 100 pg / kg / day to about 10 mg / kg / day. Thus, a therapeutically effective amount for a human 80 kg body weight may vary from about 1 mg / day to about 8 g / day, typically from about 1 mg / day to about 800 mg / day. Generally, a person with ordinary qualifications in this field, based on his or her knowledge and as described in this application, will be able to determine the effective amount of the compound of formula (I) for treating a particular disease. Compounds of formula (I) may be administered as pharmaceutical compositions in one of the following forms: oral, systemic (e.g., transdermal, intranasal, or suppository) or parenteral (e.g., by intramuscular, intravenous, or subcutaneous administration). Compositions can be prepared in the form of tablets, drops, capsules, semi-hard preparations, powders, formulations with sustained release of the active ingredient, solution, suspension, elixir, aerosol can be any other suitable composition, and in general these compositions consist of a compound of formula (I) and at least one pharmaceutically acceptable excipient. Acceptable fillers are non-toxic, support administration and do not adversely affect the therapeutic benefit of the active substance. Such fillers could be solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous, generally available to a person skilled in the art.

Solid pharmaceutical fillers contain starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicon gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, skimmed milk powder and the like. Liquid and semi-liquid fillers can be selected from water, ethanol, glycerol, propylene glycol and various oils including oil, animal, plant or synthetic (eg peanut oil, soybean oil, mineral oil, seed oil and the like). The best liquid carriers, especially for injectable solutions, are water, saline solution, dextrose and glycol aqueous solutions.

[0173] The amount of the compound of formula (I) in the composition may vary widely depending on the type of composition, the amount of the single dose, the type of filler and other factors known to those skilled in the art of pharmacology. Typically, the composition of the compound of formula (I) for treating a particular disease comprises from 0.01% w / w to 5% w / v. up to 90% sv, better from 5% sv. up to 50% vol., active substances and the rest are filler or filler. A better pharmaceutical composition can be administered as a single dose in the case of long-term treatment or as a single dose if desired, in particular for the relief of symptoms. Typical examples of compositions containing pharmaceutical compounds of formula (I) are listed below.

EXAMPLES [0174] In the following, the present invention is illustrated but not limited by the following examples, which describe the preparation of compounds of formula (I) (Examples) and intermediates (references) according to the invention. “The &quot; reference Synthesis of trifluoromethanesulfonic acid 2,2,2-trifluoro-1- (4-fluorophenyl) ethyl ester

Stage 1 50

To a stirred solution of 2,2,2,4'-tetrafluoroacetophenone (10 g, 52.1 mmol) in methanol (50 mL) was added NaBH 4 (0.98 g, 26.5 mmol) at 0 ° C. After stirring at 25 ° C for 2 hours, the reaction was stopped, 1N HCl (100 mL) was added and then extracted with ethyl ether. The ether extract was washed with brine, dried over MgSO 4 and concentrated to give 2,2,2-trifluoro-1- (4-fluorophenyl) ethanol (11.32 g) which was used in the next step without further purification. Stage 2

NaH (640 mg, 16 mmol, 60% in mineral oil) was washed twice with hexane (20 mL) and then slurried in dry diethyl ether (20 mL). A solution of 2.2) 2-trifluoro-1- (4-fluorophenyl) ethanol (1.94 g, 10 mmol) in diethyl ether (10 mL) was added at 0 ° C. After stirring for 2 hours, trifluoromethanesulfonyl chloride (1.68 g) was added at room temperature. , 10 mmol) in diethyl ether (10 mL). After two hours, the reaction was quenched by addition of NaHGO 3 solution and the product was extracted with diethyl ether. The extracts were washed with brine and dried, and the solvent was removed to give trifluoromethanesulfonic acid 2,2,2-trifluoro-1- (4-fluorophenyl) ethyl ester (3.3 g). Reference "B" Synthesis of 2,2,2-trifluoro-1 (7?) - (4-fluorophenyl) ethanol

To a solution of 2,2,2,4-tetrafluoroacetophenone (2.5 g, 13.01 mmol) in toluene (25 mL) / dichloromethane (25 mL) at -78 ° C and 1M S-methyl-CBS-oxazaborolidine catalyst (1.3 mL) , 1.3 mmol) was added freshly distilled catechol borane (1.66 mL, 15.62 mmol). The reaction mixture was maintained at -78 ° C for 16 hours, at which time 4N HCl (5 mL in dioxane) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give a precipitate. The solid precipitate was suspended in hexanes and filtered. Filtration of the hexane containing the desired product was concentrated and the residue was subjected to flash chromatography (10 hexanes: 1 ethyl acetate) to give the title compound as a colorless oil (2.2g, 87% yield). The enantiomer content was determined to be 95: 5 by chiral liquid chromatography (Chiralcel OD column, mobile phase 95 hexanes: 5 isopropanol. Main product retention time 6,757 min. Minimum isomer retention time 8.274 min.). Reference D 'Synthesis of 2 (R) - [2,2,2-Trifluoro-1- (5) - (4-fluorophenyl) ethylamino] -3-tritylpiperylpropanoic acid

To suspend S-trityl-L-cysteine (4.86 g, 13.37 mmol) in dichloromethane (97 mL, 20 mL / g AA) at room temperature, diisopropylethylamine (9.32 mL, 53.48 mmol) was added followed by trifluoromethanesulfonic acid 2. The addition of 2,2-trifluoro-1 (S) -phenylethyl ester (5.32 g, 16.04 mmol) (major enantiomer (S), 90 ee) to dichloromethane solutions in an arachis in one step. After 19 hours, the reaction mixture was concentrated on rotovap to give an oil. Diethyl ether was added and the solution was washed with 1N HCl and brine. The organic layer was dried over MgSO 4, filtered and concentrated. Purification by flash chromatography using 2 hexanes / 1 ethyl acetate / 25% acetic acid as eluant gave 2 (t) - [2,2,2-trifluoro-1 (RS) - (4-fluorophenyl) ethylamino] -3-tritylsulfanylpropanoic acid (6 g) (major diastereomers (R, S), 90 de) in the form of oil / foam. Uce ”Reference Synthesis of 2- (1-Aminocyclopropyl) -N-cyclopropyl-2-hydroxyacetamide

Stage 1 1-Aminocyclopropanecarbonitrile Chlorohydrate (6.1 g, 51.4 mmol) was stirred with 6N hydrochloric acid (500 mL) over 7 hours and then concentrated to give 1-aminocyclopropanecarboxylic acid hydrochloride as a off-white solid which was used in the next step without further purification . Step 2: A solution of 1-aminocyclopropanecarboxylic acid hydrochloride (3.6 g, 26.2 mmol) in MeOH (100 mL) in the presence of potassium carbonate (4.0 g, 28.94 mmol) was stirred at room temperature for 48 hours. After filtration, MeOH was removed under reduced pressure to give 1-aminocyclopropanecarboxylic acid (2.64 g) which was used in the next step without further purification. Step 3: 1-Aminocyclopropanecarboxylic acid (2.64 g, 26.1 mmol) and tetramethifammonium hydroxide (2.38 g, 26.1 mmol) were added to acetonitrile (150 mL). The reaction mixture became homogeneous after stirring at room temperature for about an hour. Boc20 (8.54 g, 39.2 mmol) was then added and stirring continued for 2 days. On day 3, another Boc20 dose (2.85 g, 13.1 mmol) was added and the reaction mixture was stirred for another day. Acetonitrile was removed under reduced pressure and the residue partitioned between H 2 O and Et 2 O. The water layer was washed with Et2O and then solid citric acid was added to pH ~ 3. The aqueous solution was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na 2 SO 4) and EtOAc under reduced pressure to give 1-t-butoxycarbonylaminocyclo-propanecarboxylic acid as a white precipitate (2.32 g) which was used in the next step without further purification. Step 4 52 To a solution of 1-tert-butoxycarbonylaminocyclopropanecarboxylic acid (2.32 g, 11.5 mmol) in CH 2 Cl 2 (25 mL) at 0 ° C was added N, O-dimethylhydroxylamine hydrochloride (1.24 g, 12.7 mmol), triethylamine (2.57 g, 3.54). mL, 25.4 mmol) and HATU (4.82 g, 12.7 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and then partitioned between Et 2 O and water. The water layer was extracted with Et2O. The combined organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give [1- (methoxymethylcarbamoyl) cyclopropyl] carbamic acid tert-butyl ester which was used in the next step without further purification. Stage 5 [1- (Methoxymethylcarbamoyl) cyclopropyl] carbamic acid tert-butyl ester 0.05 M solution of Et 2 O (80 mL, 4.0 mmol) was added dropwise at room temperature by lithium aluminum hydride (1.0 M Et 2 O, 5 mL, 5.0 mmol). The reaction mixture was stirred for an additional 20 minutes and then quenched by addition of 6 mL KHSO4 in aqueous solution. The layers were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with 1 N HCl, saturated NaHCO 3, and brine, dried (Na 2 SO 4) and concentrated to give (1-formylcyclo-propyl) carbamate acid tert-butyl ester as a colorless oil (393 mg) which was immediately used in the next step without further purification . Step 6 To a solution of (1-formicycloocyclopropyl) carbamic acid tert-butyl ester (393 mg, 2.12 mmol) in CH 2 Cl 2 (4 mL) was added acetic acid (191 mg, 0.182 mL, 3.18 mmol) and cyclopropylisocyanide (142 mg, 2.12 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure to give the crude acetic acid (1-tert-butoxycarbonylamino-cyclopropyl) cyclopropylcarbamoylmethyl ester which was used in the next step without further purification. Step 7: To a solution of acetic acid (1-t-butoxycarbonylaminocyclopropyl) cyclopropylcarbamoylmethyl ester in MeOH (5 mL) was added 10% NaOH (1 mL). The reaction mixture was stirred at room temperature for 2 hours and then 2.5N HCl was added to pH 7. The solution was extracted with EtOAc, rinsed with brine, dried (Na2SO4) and concentrated under reduced pressure to give [1- (cyclopropylcarbamoylhydroxymethyl) cyclopropyl] carbamic acid tert-butyl ester as a yellow oil. which was used in the next stage without further cleaning. Stage 8 [1- (Cyclopropylcarbamoylhydroxymethyl) cyclopropyl] carbamic acid tert-butyl ester solution in CH2Cl2 (5 mL) and TFA (5 mL) was stirred at room temperature for 2.5 h. The reaction mixture was concentrated and diluted with toluene to give 2- (1-aminocyclopropyl) -N-cyclopropyl-2-hydroxyacetamide.

Proceeding as described in steps 3 to 8 above, and replacing 1-aminocyclopropanecarboxylic acid with 1-aminocyclohexanecarboxylic acid affords 2- (1-aminocyclohexyl) -N-cyclopropyl-2-hydroxyacetamide. 53 53 EN 13669 T &quot; Reference Synthesis of 3-amino-N-cyclopropyl-2-hydroxy-3-methylbutyramide

Step 1 To a solution of (2-hydroxy-11-dimethylethyl) carbamic acid tert-butyl ester (284 mg, 1.5 mmol) in CH 2 Cl 2 (5 mL) was added Dess-Martin periodan (763 mg, 1.8 mmol) at 0 ° C. After 1.5 hours, 0.26M Na2S2O3 solution was added to saturated NaHCO3 (6 mL) and the mixture was stirred for 15 min. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2. The combined organic layers were dried (Na 2 SO 4) and concentrated to give (1,1-dimethyl-2-oxo-ethyl) carbamic acid tert-butyl ester as a white precipitate which was used in the next step without further purification. Step 2 To a solution of (1,1-dimethyl-2-oxo-ethyl) -carbamic acid tert-butyl ester 'CH 2 Cl 2 was added acetic acid (180 mg, 0.172 mL, 3.0 mmol) and cyclopropylisocyanide (101 mg, 1.5 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated to give the crude acetic acid 2-t-butoxycarbonylamino-1-cyclopropylcarbamoyl-2-methylpropyl ester which was used in the next step without further purification. Step 3 To a solution of 2-tert-butoxycarbonylamino-1-cyclopropylcarbamoyl-2-methylpropyl ester of acetic acid was added 10% NaOH (1.5 mL) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 3 hours and then 1N hydrochloric acid was added to pH 7. The reaction mixture was extracted with EtOAc. The organic layer was dried (Na 2 SO 4) and concentrated to give (2-cyclopropylcarbamoyl-2-hydroxy-1,1-dimethyl-ethyl) -carbamic acid tert-butyl ester which was used in the next step without further purification. Step 4: A solution of (2-cyclopropylcarbamoyl-2-hydroxy-1,1-dimethylethyl) carbamic acid tert-butyl ester in CH2Cl2 (10 mL) and TFA (5 mL) was stirred at room temperature for 4 hours. The reaction mixture was then concentrated and diluted to give 3-amino-N-cyclopropyl-2-hydroxy-3-methylbutyramide. Reference "G" Synthesis of 3-amino-N-benzyl-2-hydroxy-3-methylbutyramide

[0191] 3-Amino-N-benzyl-2-hydroxy-3-methylbutyramide was prepared according to the procedure for obtaining 3-amino-N'-cyclopropyl-2-hydroxy-3-methylbutyramide by replacing cyclopropylisocyanide with benzylisocyanide. Example 1 2-Oxo-3 (S) - {3- (pyridin-3-ylmethanesulfonyl) -2 (R) - [2,2,2-trifluoro-1 (S) - (4-fluorophenyl) ethylamino] -propionylamino} hexanoic acid cyclopropylamide synthesis

Step 1 A solution of catechol borane (19.4 mL, 182 mmol) in dichloromethane (15 mL) was added to S-methyl CBS oxazaborolidine (13 mL, 13 mmol) and 2,2,2,4-cis-fluoroacetophenone (18.2 mL, 130.13mmo!). ) at a temperature of -78 ° C for 30 minutes, the reaction mixture was stirred at -78 ° C overnight. The reaction was quenched with 4N HCl (13 mL) in dioxane at -78 ° C, warmed to room temperature and the solvent removed under reduced pressure. 10% NaHSO3 solution (200 mL) was added to the concentrate and the aqueous layer was extracted with hexane. The green layer was washed with water and dried over MgSO4. The solvent was removed under reduced pressure to give.2,2,2-irifluoro-1 (R) - (4-fluorophenyl) ethanol (20 g) as a colorless oil (90% e.e.). Step 2: NaH (11.87 g, 296.7 mmol) was added to Et 2 O (700 mL) at 0 ° C under N 2, then 2,2,2-trifluoro-1 (R) - (4-fluorophenyl) ethanol was added ( 44.3g, 228.2 mmol) of Et2O solution. The reaction mixture was stirred for 10 l. 0 ° C, then 1 hour at room temperature. A solution of trifluoromethanesulfonyl chloride (50 g, 296.7 mmol) in Et 2 O was added at 0 ° C under N 2 and the reaction mixture was stirred for 10 min. at 0 ° C and then for 3 hours at room temperature. The solvent was removed under reduced pressure and H 2 O (100 mL) was added slowly. The aqueous layer was extracted with hexane and the combined organic layer was dried over MgSO 4. The solvent was removed under reduced pressure to give trifluoro-methanesulfonic acid 2,2,2-trifluoro-1 (R) - (4-fluorophenyl) ethyl ester (70 g) as a colorless oil. Step 3: 2 (β) -amino-3-tritylsulfanylpropanoic acid (78 g, 214.6 mmol) was dissolved in CH 2 Cl 2, DIPEA (112 mL, 643.8 mmol) was added and the reaction mixture was stirred for 10 minutes at room temperature. Trifluoromethanesulfonic acid 55 55 LV 13669 2,2,2-trifluoro-1 (H) - (4-fluorophenyl) ethyl ester (70 g, 214.6 mmol) and CH 2 Cl 2 were added and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in Et2O and washed with 1N HCl and brine and dried over MgSO 4. The solvent was removed to give 2 (R) - [2,2,2-trifluoro-1 (S) - (4-fluorophenyl) ethylamino] -3-tritylsulfanylpropanoic acid (90 g) as a yellow solid. Step 4: 2 (F) - [2,2,2-Trifluoro-1 (S) - (4-fluorophenyl) ethylamino] -3-tritylsulfanylpropanoic acid (5.4 g, 10 mmol) was dissolved in CH 2 Cl 2 and added to TFA ( 3.1 mL, 40 mmol) at 0 ° C under N 2. Et 3 Si (3.2 mL, 20 mL) was added at 0 ° C under N 2 and the reaction mixture was warmed to room temperature. After stirring for 2 hours, the solvent was removed under reduced pressure and the residue was dissolved in 1N NaOH (120 mL). The water layer was extracted with arphexane. To the aqueous solution was added dioxane (120 mL), 3-picolyl chloride hydrochloride (1.97 g, 12 mmol), and tris (2-carboxyethyl) phosphine hydrochloride (280 mg, 1 mmol). The reaction mixture was stirred at room temperature overnight. Dioxane was removed under reduced pressure. The pH of the water layer was adjusted to pH3 and extracted with ethyl acetate. The combined organic layer was dried over MgSO 4, filtered and concentrated under reduced pressure to give 3- (pyridin-3-ylmethanesulfonyl) -2 (R -) * [2,2,2-trifluoro-1 (S) - (4-fluorophenyl) - Ethylamino] propane acid, which was used in the next step without further purification. Step 5: To a solution of 3- (pyridin-3-ylmethanesulfonyl) -2 (R -) - [2,2,2-trifluoro-1 (S) - (4-fluoronyl) -ethylamino] propanoic acid in methanol (10 mL) ΟΧΟΝΕ® (4.68 g, 10 10 mL H 2 O) aqueous solution. The reaction mixture was stirred at room temperature. After 2 hours, the solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to give 3- (pyridin-3-ylmethanesulfonyl) -2 - ((7) [2,2,2-irifluoro-1 (S) - (4-fluorophenyl) ethylamino] propanoic acid, which was used without further purification. cleaning was used in the next stage. Step 6: 3- (Pyridine-3-ylmethanesulfonyl) -2- (1 H) -2-trifluoro-1 (S) - (4-fluorophenyl) ethylamino] propanoic acid (420 mg, 1 mmol) ) and a mixture of cyclopropylamide (186 mg, 1 mmol) of 3 (S) -amino-2-hydroxyhexanoic acid as described in PCT application publication no. WO-02/18369 as a compound xiii to which HBTU (455 mg, 1.2 mmol) and NMM (0.44 mL, 4 mmol) were added in acetonitrile and stirred at room temperature overnight. Saturated NH4Cl (10 mL) and ethyl acetate (10 mL) were added and, after 20 minutes, the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over MgSO 4, filtered and filtered under reduced pressure to give 2-hydroxy-3 (S) - {3- (pyridin-3-ylmethanesulfonyl) -2 (R) '[2.2, 2-Trifluoro-1 ($) - (4-fluorophenyl) -ethylamino] propionylamino} hexanoic acid cyclopropylamide, which was used in the next step without further purification. Step 7 56 2-Chloro-3 (S) - {3- (pyridin-3-ylmethanesulfon) -2 (R) - [1,2,2-trifluoro-1 (5) - (4-fluorophenyl) ) -Ethylamino] propionylamino} hexanoic acid cyclopropylamide (590 mg, 1 mmol) in methylene chloride was slowly added to DMP. The reaction mixture was stirred at room temperature for 30 minutes and then added to 0.26 M Na2S2O3 saturated NaHCO3. The reaction mixture was stirred for 20 minutes. The aqueous layer was extracted with methylene chloride and the combined organic extracts were dried over MgSO 4, filtered and concentrated to give 2-oxo-3 (S) - {3- (pyridin-3-ylmethanesulfonyl) -2 (R) - [2.2.2- trifluoro-1 (S) - (4-fluorophenylthiylamino) -propionylamino] -hexanoic acid cyclopropylamide purified on a flusholone (2% MeOH-CH2Cl2) to give the pure product as a yellow solid.

1 H-NMR (DMSOd 6): δ 0.80 (m, 12H), 2.02 (m, 1H), 3.3-3.7 (b, 3H), 4.00 (m, 1H), 4.46 (m, 1H), 4.79 ( m, 2H), 7.25 (m, 2H), 7.50 (m, 2H), 7.65 (b, 1H), 7.72 (d, 1H), 4.01 (d, 1H), 8.71 (m, 3H). LC-MS: 587 (M + 1), 585, (M-1), 609 (M + 23).

As described above, and replacing 3-picolyl chloride with cyclopropylmethyl bromide, 2-oxo-3 (3) - {3- (cyclopropylmethanesulfonyl) -2 (t)-[2,2,2-trifluoro-1] is obtained. (S) - (4-Fluorophenyl) ethylamino] -propionylamino} hexanoic acid cyclopropylamide (Compound 1). 1 H-NMR (DMSO-d 6): δ 0.32-0.41 (m, 2H), 0.53-0.67 (m, 6H), 0.81 (t, J = 7.2Hz, 3H), 1.06-1.38 (m, 4H), 1.52 -1.61 (m, 1H), 2.69-2.76 (m, 1H), 2.98 (dd, J = 2.8Hz, J = 14.8Hz, 1H), 3.19 (dd, J = 8Hz, J = 14Hz, 1H), 3.28 3.50 (m, 3H), 3.82-3.88 (m, 1H), 4.37 (quint, J = 7.6 Hz, 1H), 4.70-4.76 (m, 1H). 7.22 (t, J = 8.4Hz, 2H), 7.43 (dd, J = 5.6Hz, J = 8.4Hz, 2H), 8.51 (d, J = 7.2Hz, 1H), 8.73 (d, J = 5.2 Hz, 1H). LC-MS: 550 (M + 1), 548, (M-1) · Example 2 2-Oxo-3 (S) -3- [2 (t?) - (2,2,3,3,3) pentafluoropropylamino) -3- (pyridyl-3-ylmethanesulfonyl) propionylamino] pentanoic acid cyclopropylamide synthesis

Step 1: 2,2,3,3,3-pentafluoropropan-1-ol (1.5 g, 10.0 mmol) for methylene chloride (75 mL) at -78 ° C and DIPEA (6.1 mL, 35.0). mmol) (CF 3 SO 2) 20 (1.78 mL, 10.5 mmol) was added. After 2.5 hours, S-tritylcysteine was added in one shot and the reaction mixture was stirred at 0 ° C for 80 minutes. The reaction mixture was stirred at room temperature for 18 hours and then concentrated on a rotovap. Ethyl acetate was added and the reaction mixture was washed with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated. I mean. The product was purified by 57 57 LV 13669 flush chromatography (3 hexane / 1 ethyl acetate + 1% acetic acid) to give 2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3-tritylsulfanylpropanoic acid (3.29 g). Step 2: 2 (R) - (2,2,3,3,3-Pentafluoropropylamino) -3-triylsulfanylpropanoic acid (1.05 g, 2.12 mmol) in methylene chloride (15 mL) was added to TFA (0.653 mL, 8.48 mmol). ), followed by triethylsilane (0.677 mL, 4.24 mmol). The reaction mixture was stirred for 1.5 h at room temperature and then concentrated on a rotovap. To the residue was added 2N NaOH solution (20 mL) and the reaction mixture was extracted with hexane. To the NaOH layer was added tris (2-carboxytriethyl) phosphorus hydrochloride (60 mg) followed by 3-picolyl chloride hydrochloride (348 mg, 2.12 mmol). After 1.5 hours the reaction was acidified with arconc. HCl to pH = 4 and extracted with ethyl acetate. The organic layer was dried and concentrated to give 2 (f) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfonyl) propanoic acid (530 mg). Step 3: 2 (R) - (2,2,3,3,3-Pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfonyl) propanoic acid (151 mg, 0.44 mmol), 3 (S) -amino To a solution of 2-hydroxypentanoic acid cyclopropylamide hydrochloride (92 mg, 0.44 mmol), EDC (102 mg, 0.66 mmol) and HOBt (71 mg, 0.53 mmol) was added N-methylmorpholine (0.194 mL, 1.76 mmol). The reaction mixture was stirred for 2 hours and then diluted with ethyl acetate and washed with sodium bicarbonate solution. The organic layer was concentrated to give cyclopropylamide of 2-hydroxy-3 (S) - [2 (t) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfonyl) propionylamino] pentanoic acid. (170 mg). Step 4 2-Hydroxy-3 (S) - [2 (R) - (2,2,3,3,3-peniafluoropropylamino) -3- (pyridin-3-ylmethanesulfanyl) propionylamino] Cyclopropylamide of penic acid (170 mg, 0.34 mmol) was added to a solution of NMP (209 mg, 0.34 mmol) in water. After 2 hours, ΟΧΟΝΕ® (105 mg, 0.17 mmol) was added again with water and a little methanol. Another 1h 40 min. the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was concentrated to give cyclopropylamide of 2-hydroxy-3 (S) - [2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3- (pinnin-3-ylmethanesulfonyl) propionylamino] pentanoic acid (176 mg) ). Step 5 Heterogeneous 2-Hydroxy-3 (S) - [2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfonyl) propionylamino] pentanoic acid cyclopropylamide (176 mg, 0.33 mmol) and methylene chloride were added Desa-Martin periodin (183 mg, 0.43 mmol). The reaction mixture became heterogeneous in a few minutes. After 3 hours, acetonitrile (3 mL) was added followed by NMP (6 mL) to give a homogeneous reaction. At this point, Desa-Martin's periodin (100 mg) was added again. After stirring for another 70 minutes, the reaction mixture was diluted with ethyl acetate and rinsed with sodium bicarbonate solution. The organic layer was separated and concentrated. Purification by flash chromatography (95% methylene chloride / 5% methanol) gave a solid which was suspended in a 1: 1 IPA / ethanol mixture and evaporated to dryness to give 2-oxo-3 (S) -3- 58 [2 (/ 7)] - (2,2,3,3,3-Pentafluoropropylamino) -3- (pyridyl-3-ylethanesulfonyl) propionylamino] pentanoic acid cyclopropylamide (87 mg) Example 3 N- (1-Cyclopropylaminocalylcyclopropyl) - Synthesis of 3-cyclopropylmethanesulfonyl-2 (Ej- [2,2,2-trifluoro-1 (S) - (4-fluorophenyl) ethylamino] propionamide \ t

βθ2

Step 1: 3-Cyclopropylmethanesulfonyl-2 (R) - [2,2,2-irifluoro-1 (1S) - (4-fluorenyl) ethylamino] propanoic acid (148 mg, 0.42 mmol) prepared as described above In Example 1, substituting picolinyl chloride with cyclopropylmethyl bromide and 2- (1-amino-cyclopropyl) -N-cyclopropyl-2-hydroxyacetamide (108 mg, 0.63 mmol) in N-methylpyrrolidine (6 mL) was added at 0 ° C. V / N-Ethylpropi (amine (272 mg, 0.37 mL, 2.11 mmol) and HATU) The reaction mixture was stirred for 4 h at room temperature The reaction mixture was diluted with EtOAc and rinsed with H 2 O. The organic layer was dried (Na 2 SO 4) and concentrated. Obtaining N- [1- (dichloropropylcarbamoylhydroxymethyl) cyclopropyl] -3-cyclopropylmethylsulfanyl-2- [2,2,2-trifluoro-1- (4-fluorenyl) ethylamino] propionamide converted to the parent compound as described above 2. Example 4 and Step 5. MS (534.2 M + 1, 532.1 M-1).

By performing the procedure described in Example 3, but replacing 2- (1-amino-cyclopropyl) - [(cyclopropyl-2-hydroxyacetamide) with 3-amino-N-benzyl-2-hydroxy-3-methylbutyramide, V-Benzyl-3- {3-cyclopropylmethanesulfonyl-2 (R) - [2,2,2-trifluoro-1 (S) - (4-fluorenyl) ethylamino] propionylamino} -3-methyl-2-oxo-butyramide. · MS (586.3 M + 1, 584.3 M-1).

While performing the procedure described in Example 3, substituting 2- (1-amino-cyclopropyl) -N-cyclopropyl-2-hydroxyacetamide with 3-amino-N-benzyl-2-hydroxy-3-methylbutyramide and 2 \ t (R) - [2,2,2-Trifluoro-1 (S) - (4-fluorophenyl) ethylamino] -3-tritylsulfanylpropanoic acid with 2 (R) - [2,2,2-trifluoro-1 (R) - ( 4-Fluorophenyl) ethylamino] -3-tritylsulfanylpropanoic acid, obtained as N-benzyl-3- {3-cyclopropylmethanesulfonyl-2 (R) - [2,2,2-trifluoro-1 (1H) - (4-fluorophenyl) ethylamino ] propionylamino} -3-methyl-2-oxo-butyramide. N-Benzyl-3- {3-cyclopropylmethanesulfonyl-2- [2,2,2-trifluoro-1- (4-fluoro-phenyl) -ethyl] -propionylamino} -3-methyl-2-oxobutyramide MS (586.1 M) +1, 584.1 M-1).

By performing the procedure described in Example 3, but replacing 2- (1-amino-cyclopropyl) -N-cyclopropyl-2-hydroxyacetamide with 3-amino-cyclopropyl-2-hydroxy-3-methylbutyramide, 59 \ t 59 LV 13669 AAcyclopropyl 3,3-cyclopropylmethanesulfonyl-2 (R) - [2,2,2-trifluoro-1 (S) - (4-fluorophenyl) ethylamino] propionylamino} -3-methyl-2-oxobutyramide. MS (536.0 M + 1, 534.2 M-1). Example 4 Synthesis of cyclopropylamide of 3 (S) - [3-cyclopropylmethanesulfonyl-2 (R) - (2,2,3,3,3-pentafluoropropylamino) -propionylamino] -2-oxopentanoic acid

Step 1: 2,2,3,3,3-pentafluoropentan-1-ol (1.5 g, 10.0 mmol) and DIPEA (6. 1 mL, 35.0 mmol) in dichloromethane (75 mL) at -78 ° C C, (triflic) (CFsSC4O (1.78 mL, 10.5 mmol) was added dropwise. After 2 h 20 min, the reaction mixture was treated with S-triilcysteine and stirred continuously for 1 h at 15 min at 0 ° C and then at 19 h. The reaction mixture was concentrated on a rotovap and the residue was subjected to flushchromatography (3: 1, hexane / ethyl acetate / 1% acetic acid) to give 2 (t) - (2,2,3,3,3-pentafluoropropylamino) -3-iridylsulfanyl-propanoic acid ( Step 2: 2 (t) - (2,2,3,3,3-Pentafluoropropylamino) -3-tritylsulfanylpropanoic acid (1.05 g, 2.12 mmol) in dichloromethane was added to TFA (0.653 mL, 8.48 mmol), then triethylsilane (0.677 mL, 4.24 mmol) The reaction mixture was stirred for 1 h at room temperature for 20 min and then concentrated on a rotovap to which 2N NaOH and hexanes were added. Cyclopropylmethyl bromide (0.206 mL, 2.12 mmol) was added to the NaOH layer. The reaction mixture was stirred for 17 h. at room temperature and then acidified with 1N HCl and the product extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 2 (t) - (2,2,3,3,3-pentafluoropropylamino) -3-cyclopropylmethanesulfonyl) propanoic acid (428 mg). Step 3 '2 (R) - (2,2,3,3,3-Pentafluoropropylamino) -3- (cyclopropylmethanesulfonyl) propanoic acid (150 mg, 0.49 mmol), 3 (S) -amino-2-hydroxy N-methylmorpholine (0.215 mL, 1.96 mmol) was added to a mixture of cyclopropylamide hydrochloride hydrochloride (102 mg, 0.49 mmol), EDO (114 mg, 0.74 mmol) and HOBt (79 mg, 0.59 mmol). The reaction mixture was stirred for 2 hours at room temperature and then diluted with ethyl acetate and rinsed with sodium bicarbonate solution. The organic layer was dried and concentrated to give cyclopropylamide of 2-hydroxy-3 (S) - [2 (t) - (2,2,3,3,3-pentafluoropropylamino) -3- (cyclopropylmethanesulfonyl) propionylamino] pentanoic acid ( 169 'mg). Step 4: [0213] 2-Hydroxy-3 (S) - [2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3- (cyclopropylmethanesulfonyl] propionylamino] -pentanoic acid for cyclopropylamide (169 mg, 0.37 mmol) for NMP (5 mL) was added ΟΧΟΝΕ (342 mg, 0.56 mmol) aqueous solution After stirring for 2 h at room temperature, ΟΧΟΝΕ (228 mg) aqueous solution was added again with methanol (5 mL) After stirring for 2 h, the reaction mixture was diluted with ethyl acetate. and washed with saturated brine, the organic layer was separated, dried and concentrated to give a white solid, to which was added dichloromethane (10 mL) and Desa-Martin periodan, to which was added acetonitrile (3 mL) followed by NMP (6 mL). After 5 hours, the reaction mixture was diluted with ethyl acetate and rinsed with sodium bicarbonate solution, the organic layer was dried and concentrated to give a crude product. White solid was added to this white substance and the mixture was heated to reflux. The homogeneous mixture was still left to cool to room temperature and filtered to give the title compound as a white solid (115 mg). M. pt 196.1-196.7 ° C.

As described above, the following compounds were obtained: N-Cyclopropyl-3S- {3-benzenesulfonyl-2H- [2,2,2-trifluoro-1S- (4-fluorophenyl) ethylamino] propionylamino} -2-oxopentanamide , LC-MS 558 (M + H) and N-Cyclopropyl-3S- [3-cyclopropylmethanesulfonyl-2R '- (2,2,3,3,4,4,4-heptafluorobutylamino) propionylamino] -2-oxopentanamide, LC-MS 542 {M + H). Example 5 'N-Cyclopropyl-3S- {4-methanesulfonyl-2S- [2,2,2-irifluoro-1S- (4-fluorophenyl) ethylamino] butyrylamino} -2-oxopentanamide synthesis [0215] (S) Methyl -2-Amino-4-methylsulfanylbutyrate hydrochloride (750 mg, 3.76 mmol) and 2,2,2-trifluoro-1- (4-fluorophenyl) ethanone (721 mg, 3.76 mmol) were dissolved in methanol (15 mL) and potassium carbonate (1.04 g, 7.52 mmol) was added to the solution. The mixture was stirred at 55 ° C for 23 hours and then concentrated to dryness in a rotovap. The residue was combined with toluene and the mixture was concentrated to dryness on a rotovap. The residue was combined with acetonitrile (10 mL) and the mixture was stirred at about 30 ° C. Zinc borohydride prepared by adding 1M zinc chloride solution in ether (5.64 mL) to a mixture of sodium borohydride (427 mg, 11.28 mmol), stirring ether (10 mL) and then stirring for 19 h, was added to the reaction mixture with stirring for about 7 h. at a reduced temperature and then for a further 16 hours at room temperature. 1N HCl diluted with ethyl acetate was added to the reaction mixture and washed with brine (2X50mL).

The organic layer was dried and concentrated to give 2S- [2,2,2-trifluoro-IS- (4-fluorophenyl) ethylamino] -4-methylsulfanyl-uric acid (1.15 g) as a solid.

2S- [2,2,2-Trifluoro-1S- (4-fluorophenyl) ethylamino] -4-methylsulfanedioic acid (150 mg, 0.46 mmol), cyclopropyl-3S-amino-2-hydroxypentanamide hydrochloride (106 mg) , 0.51 mmol), EDC (132 mg, 0.69 mmol) and HOBt (75 mg, 0.55 mmol) were combined with DCM (10 mL) and the mixture was stirred at room 61 61 LV 13669, while N-methylmorpholine (0.253 mL, m.p. 2.3 mmol). The mixture was stirred for 2 hours 15 minutes and then diluted with ethyl acetate. The mixture was washed with sodium bicarbonate solution (2X35mL) and the organic layer dried and concentrated to give N-cyclopropyl-2-hydroxy-3S- {4-methanesulfonyl-2S- [2,2,2-trifluoro: 1S- (4-fluorophenyl) ) ethylamino] butyrylamino} pentanamide (188 mg) as a white solid.

N-cyclopropyl-2-hydroxy-3S- {4-methanesulfonyl-2S- [2,2,2-trifluoro-1 S- (4-fluorophenyl) ethylamino] butyr [amino] pentanamide (188 mg, 0.39) mmol) was dissolved in 1-methyl-2-pyrrolidinone (5 mL) and the solution was stirred at room temperature while the oxone aqueous solution (5 mL, 434 mg, 0.71 mmol) was added. The mixture was stirred for 1 h. 45 min. and then diluted with ethyl acetate. The mixture was washed with brine (3x25mL) and the organic layer was dried and concentrated. The residue was dissolved in 1-methyl-2-pyrrolidinone (5 mL) and Desa-Martina Periodane (232 mg, 0.55 mmol) was added to the solution. The reaction was allowed to proceed for 1 hour and then diluted with ethyl acetate. The mixture was washed with sodium bicarbonate solution (3x30mL) and the organic layer was dried and concentrated. The residue was combined with ether and added to a solid. Scrape off and filter the mixtures to give N-cyclopropyl-3S- {4-methanesulfonyl-2S- [2,2,2-trifluoro-1S- (4-fluorophenyl) ethylamino] -butyrylamino} -2-oxopentanamide (114 mg) white as a solid (mp 152.5-153.5 ° C). LC-MS 510 (M + H).

Biological Examples Example 1 Cathepsin B Test Various concentrations of test compound solutions were prepared in 10 µL dimethylsulfoxide (DMSO) and then diluted to give test buffer (40 µL containing N, N-bis (2-hydroxyethyl) -2- aminoethane) phosphoric acid (BES), 50 mM (pH 6); polyoxyethylene sorbitan monolaurate, 0.05%; and dithiothreitol (DTT), 2: 5 mM). Human cathepsin B (0.025 pMol 25 pL test buffer) was added to the diluted mixtures. The test solutions were stirred for 5-10 seconds on a shaker plate, sealed with caps and kept at room temperature for 30 minutes. Z-FR-AMC (20 nMol 25 pL test buffer) was added to test solutions and hydrolysed the course with a spectrophotometer (λ 460 nm) for 5 minutes. Apparent inhalation constants (Kj) were calculated by enzymatic curves with standard mathematical methods.

The compounds described in the invention were tested according to the above test and found to inhibit cathepsin B activity. EXAMPLE 2 Cathepsin K Assay [0220] Solutions of various concentrations of test compounds were prepared in 10 µL of dimethylsulfoxide (DMSO) and then diluted to give a test buffer (40 pL containing MES, 5.0 mM (pH 5.5); EDTA, 2.5 mM; DTT, 2.5 mM). Human cathepsin K (0.0906 pMol 25 pL test buffer) was added to the diluted mixtures! The test solutions were stirred for 5-10 seconds on a shaker plate, sealed with caps and kept at room temperature for 30 minutes. Z-Phe-Arg-AMC (4 nMol 25 pL assay buffer) was added to the test solutions and hydrolysis 62 was observed with a spectrophotometer. (λ 460 nm) 5 minutes. The apparent inhibitory constants (Kj) were calculated from the curves of the enzymatic process with standard mathematical methods.

The compounds described in the invention were tested according to the above test and found to inhibit the activity of cathepsin K. Example 3 Cathepsin L Assay Various concentrations of test compound solutions were prepared in 10 µL dimethylsulfoxide (DMSO) and then diluted to give test buffer (40 pL containing MES, 50 m'M (pH 5.5); EDTA, 2.5 mM) ; and DTT, 2.5 mM). Human cathepsin L (0.05 pMol 25 pL assay buffer) was added to the diluted mixtures. The test solutions were stirred for 5-10 seconds on a shaker plate, sealed with caps and kept at room temperature for 30 minutes. Z-Phe-Arg-AMC (1 nMol 25 p L test buffer) was added to the test solutions and hydrolysed the course with a spectrophotometer (λ 460 nm) for 5 minutes. The apparent inhibitory constants (Kj) were calculated from the curves of the enzymatic process with standard mathematical methods.

The compounds described in the invention were tested according to the above test and found to inhibit the activity of cathepsin L. Example 4 Cathepsin S Assay Various concentrations of test compound solutions were prepared in 10 µl of dimethylsulfoxide (DMSO) and subsequently diluted to give a test buffer (40 µl containing MES, 50 mM (pH 6.5); EDTA, 2.5). mM; and NaCl, 100 mM); β-mercaptoethanol, 2.5 mM; and BSA, 0.00%. Human cathepsin O (0.05 pMol 25 pL test buffer) was added to the diluted mixtures. The test solutions were stirred for 5-10 seconds on a shaker plate, sealed with caps and kept at room temperature for 30 minutes. Z-Val-Val-Arg-AMC (4 nMol 25 pL test buffer containing 10% DMSO) was added to the test solutions and hydrolysed the course with a spectrophotometer (λ 460 nm) for 5 minutes. The apparent inhibitory constants (Kj) were calculated from the curves of the enzymatic process with standard mathematical methods.

[0225] The compounds described in the invention were tested according to the above test and found to have a cathepsin S inhibitory activity of less than or equal to 100 nm. Example 5 Cathepsin F assay [0226] Solutions of various concentrations of test compounds were prepared in 10 pL dimethylsulfoxide (DMSO) and then diluted to give test buffer (40 pL containing MES, 50 mM (pH 6.5); EDTA, 2.5 mM; NaCl, 100 mM); DTT, 2.5 mM; and BSA, 0.01% .The diluted mixtures were added 'human cathepsin F (0.1 pMol 25 pL assay buffer). The test solutions were stirred for 5-10 seconds on a shaker plate, sealed with caps and kept at room temperature for 30 minutes. Z-Phe-Arg-AMC (2 nMol 25 pL assay buffer containing 63 U of 13669 10% DMSO) was added to test solutions and hydrolysed by spectrophotometer (λ 460 nm) for 5 minutes. The apparent inhibitory constants (Kj) were calculated by enzymatic process curves with standard mathematical methods. The compounds described in the invention were tested according to the above test and found to inhibit cathepsin F activity. Example 1

Typical pharmaceutical compositions containing a compound of formula (I)

ORAL USE! 10-100 mg 105 mg 18 mg supplemented to 100 mL

THE COMPOSITION

Compound of formula (I) Citric acid monohydrate Sodium hydroxide Additive flavor enhancement Water

COMPOSITION FOR INTRAVENOUS USE

Compound of Formula (I) Dextrose Monohydrate Citric Acid Monohydrate Sodium Hydroxide Water Injection 0.1-10 mg Sufficient For Isotonic Formulation 1.05 mg 0.18 mg

sufficient 1.0 mL

CONTAINS TABLETS

Compound of formula (I) '1%

Microcrystalline cellulose 73%

Stearic acid 25%

Silicon Dioxide 1% [0228] This invention has been described in much detail, illustrating and illustrating examples for the sake of clarity and understanding. A person with a qualification in this field will obviously be able to make changes and modifications in practice within the attached claims. Thus, it should be understood that the above description is illustrative and not restrictive. Thus, the contents of the invention should be determined not by the description of the invention but by the claims appended hereto, together with all equivalents to which these claims give rise. 1 1LV 13669

ALPHA KETOAMEDE COMPOUNDS AS CYSTEINE PROTEAS DVHIBITOR CROSS-REFERENCES TO RELATED APPLICATIONS [0003] 60 / 663,910 filed March 21,2005 and Provisional Patent Application No. 60 / 684,623 filed May 24, 2005, both of which are incoïpoiated berein by reference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDER4LLY SPONSOSED RESEARCH OR DEVELOPMENT

NOT APPLICABLE

REFERENCE TO A "SEQUENCE LISTING," ATABLE, OR A COMPUTER PROGRAM LISTING APPENDK SUBM2TTED ΟΝ A COMPACT DISK

NOT APPLICABLE

MELE »OF THE INVENTION

[0094] 'Tbe present invention is directed to inhibitors of cysteine proteases, inparticular, catbepsins B, K, L, F, and S and are tberefore usefilter in these diseases. These compounds andprocssses for prepaiing thein.

STATE OF THE ART

[0005] Cvsteine proteases represent a class of peptidases. Cysteine proteases are associated with the abnormal degradation and processing of protein, eg, mayhave pathological consequences. Cysteine proteases are associated witb a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy and others. For example, increased cathepsin B Ievels and redistribution of the enzyme are found in tumors; thus, a role for the enzyme in tmnor invasion and metastasis. In 2 additions, aberrant cathepsin implants in rheumatoid arthritis, osteoarthritis, pneumocystis caiinii, acute pancreatitis, inflammatory airway disease and bone and joint disorder.

The prominent expression of cathepsin in osteoclast and osteoclast-related multinucleated celis and iis high collagenolytic activity suggestion of osteoclast-mediated bone resorption and hence in osteoporosis. In addition, cathepsin K expression in the lung and iis elastinolytic activity suggest that a role in pulmonary disorders as well.

Cathepsin L is implicated in norms for lysosomal proteolysis as well as in several disease states, including, but not limited to, metastasis of melanomas. Cathepsin S is implicated in Alzheimer's Disease and Cramam Autoimmune Disorders, including Multiple Sclerosis, Pemphigus Vulgaris, Graves' Disease, Myasthenia Grayis, Systemic Lupus Erythematosus, Rheumatoid Arthritis, Neuronathic Pain, and Hashimoto's Thyroiditis. In addition, cathepsin is implicated in: allergic disorders, including but not limited to asthma; and allogeneic immune reponses, including but not limited to, rejecrion of organ transnlants or tissue grafts.

Which inhibit cathepsins, in particular molecules which inhibit cathepsins, and inhibit cathepsins. B, K, L, F, and / or S will iherefore be useful as therapeutic agent.

SUMMARY OF THE INVENTION

In one aspect, a compound of Formula (I):

R

R8 is H: R1 is hydrogen or alkyl; R2 is cycloalkyl, cycloaIky3aIkyi, araBcy, heteroaryl, orheteroaralkyl substituted with one or two substituents inaependently selected from alkyl, a! Koxy, orhalo; R3 is hydrogen, alkyl or alkoxyalkyl; 3 3LV13669 R4 is aBcyl; or R 3 and R 4 togeiher with the carbon atom to which they are attached for cycloalkylene optionally substituted with alkyl, alkoxy, alkyl, hydroxyl, acyl, cycloalkyl, cycloalkyl, oralkylalkyl; R5 is acyl, haloalkyl substituted substituted cycloalkyl, allyl, beterooyl, or heterocycloalkyl3, cycloalkylalkyl3 aralkyl, heteroarylalkyl, heterocycloalkylalkyl, - (alkylene) -X-R9 (where X is -O-, S-, -SO-, -SO2- , -CONH-, -NHCO-, or -NHSO 2 - and R 9 is albyl, haloalkyl, cycloalkyl, cycloalkoxyalkyl aryl, aralkyl, beteroaryl; heteroaralkyl, heterocycloalkyl, or heterocydoalkylalkyl), or - (a ^ Ien-thaloalph / lenej) -R10 (whereX 'is -O-, -S-, -SO-, -SO2-, -CONH-, -NHCO-, or -NHSO2- and R10 is cyloo] yl, aryl, heteroaryl, or heierocycloJkyl), selected from one, two, or three Ra or selected from alky, haloIkyl, a] i; oxy, hydroxy, halo: oxy, cyano, balo, carboxy, or alkoxycarbcnyl; or optionalIy substituted with one or two Rb independenilv seieeted nrom hydrogen, a3kyl, haloalkylo alkoxy, hydroxy, haloalkoxyj balo, caxboxy, or aikoxycarbonyl and oneRc selected from hydroxya! kyī, alioxya! kyi, anainoallcy !, siyl, heteroaryl, aralkyl, heteroaryl &lt; yl, cycloaUryl, cycloalicyl3yl, heterocycloalkyl, heterocycloalkylalkyl, acyl, acylalkyl. aiyloxycarbonyl, aralky3oxycarbonyl, beieroaiyloxycarbonyl, heieroaralkyloxycarboūyl, heierocyxloalkyloxycarbonyi, cycloalkyl! kyloxycarbonyl, aryloxy, heteroaryloxy, ara! kyloxy, heieroaral] cyloxy, aminocarbonyl, armriosulfonyl, or -SO2R11 (vriiere R11 is alkyl, cycloalkyl, aryl, heteroaiyl, or heierocycloaIkyļ); and furthermore, selected from alkyl, a3, sulfonyl, baloalkyl, atxyxy, bydroxy, haloalkoxy, or balo; R6 is haloalkyl; R 7 is hydrogen, alkyl, 01 haloalkyl; and R8 is bydxogen, allcyl, haloalkyl, cycloalkyl, aryl, beteroaryl, heterocycloalkyl attached via carbon atoms, aromatic or alicyclc ring in R is optionally substituted with one, tvo, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkylcarbonyl, allcoxycarbonyl, carboxy, cyano, alkylsulfonyl, a] cyclopropylamino or aminocarbonyl, or aminosulfonyl; or a phannaceuticaUy acceptable salts of a compound of the invention. A compound of the invention is a compound of the invention.

A method of treating an animal with a cysteine protease, which is a method of treating an animal. One or more suitable excipients for the formula (T).

[0012] In a fourth aspect, this invention is directed to processes for preparing compounds of Formula (Γ).

In a patient, a patient is a compound of formula (I). ) or aphannacsuiica31y acceptable salt. Preferably, the immune response is mediated by MHC class ules molecules. The compound of this invention. can be admirdstered prior to, simultaneonsly. or after the therapy. Preferablv, therapy iovolves treatment with a biologic. Preferably, the therapy involves treatment of small molecules.

Preferably, the biologic is a protein, more an antibody, more preferably a monoclonal antibody. More preferrably, the biologic is Remicade®, Refacto®, Referon-A®, Factor VHI, Factor VH, Betaseron®, Epogen®, Enbrel®, interferon beta, Βοΐοχ®,

Fabrazyme®, Elspai®, Cerezyme®, Myobioc®, Aldurazyme®, Verluma®, interferon alpha, Humira®, Aranesp®, Zevalin® or OKT3.

Preferably, low molecular weight heparin, procainamide or hydralazine.

A sixth aspect of the treatment of the immune response to the animal, which is a method of treatment of the animal. of a compound of the Fonnula 5 5 EN 13669 In a seventh aspect, a method of conducting a clinical trial for a biologic is administered. Clinical trial of a compound of Formula (Γ) or a.

In a eigth aspect, a method of treating a patient undergoing treatment with a biochemistry with a compound of Formula (1) patient.

In a ninth aspect of a biology in a ninth aspect of a biology, a biology of a biology in the body Formula (I) or apharm a acceptable salt.

[0020] In a tenth aspect, a method of improving the biological activity of an animal is a compound of formula (I) or a ph2iniaceutically acceptable salt.

[0021] In an eleventh aspect, the present invention is directed to the use of a medicament. Prefsrabiy, the medicament is for use in the treatment of a disease mediated by Cathepsin S.

3: a twelfih aspect of the invention of the compound of the invention. iromune response caused by the biologic. Preferably, the compound of the invention is administered concomitantly with the biologic agent. Preferably, the compound of the invention is administered after the administration of the biologic agent.

Detailed Description of the Invention D.efLnitions: [0023] Unless otherwise stated, the following claims are made. 6 &quot; AJicyclic &quot; cycloalyl and heterocycloalkyl rings as defined herein.

&Quot; A! Kyl &quot; Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, teriAmtjl, and the like.

[0925] &quot; AIkylene ', unless indicated by an aliphatic, divalent radical having the number one to six carbon atoms, eg, meihylene (-CH2O1 ethylene (-CH2CH2-), trimethylene (- CH2CH2C% -), tetramethylene (-CH2CH2CH2CH2-) 2-methyltetramethylene (-CH2CH (CH3) CH2CH2-), pentamethylene (-CH2CH2CH2CE7CH, -), and the like.

&Quot; Alkylcarbonyl &quot; means -SO 2 Rradical where R is alkyl as defined herein, methylsulfonyl, nemhylsulfonyl, and the like.

&Quot; Alkylsulfonylminone means -NHSO2Rradical Rf is as defined herein, for example, methylsulfonylamino, ethylsuylphenylamino, and the like.

&Quot; Aficoxy &quot; refers to a-OR radical v. R is an alkyl group as defined above, methoxy, ethoxy, and the like.

&Quot; Alkoxyalkyl &quot; 1, 2-methoxy-ethyI, as defined above, eg, 2-methoxy-ethyI, means a linear monovalent hydrocarbon radical of one to six carbon atoms. l-, 2-, or 3-methboxypropyl, 2-ethoxyethyl, and the like.

&Quot; -Alkoxycarbonyl &quot; refer to a-C (O) ORradical where R is an alkyl group as defined above, methoxycarbonyl, ethoxycarbonyl, and the like.

"Aminoallcyr" means a linear monovalent hydrocarbons radical of one to six carbon atoms or a branched monovalent hydrocarbons radical of three to six carbons substituted by at least one, preferably one or two, -NRR 'where R is hydrogen, alkyl, acyl, hydroxyalkyl, alkoxy] yl, aryl, aralkyl, heteroaryl; defined herein, aminomethyl, methylaininoethyl, dimethvlaminoethyl, 1,3-diaminopropyl, acetylaminopropyl, and the residue.

&Quot; Acrylic to a -COR radical where R is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, axalkyl3 heteroaryl, heroeraralkyl, or heterocycloalkyl as defined herein, e.g., phonnyl, acetyl, trifluoroacetyl, benzoyl, piperazine-l- ylcarbonyl, and the like. Wben R is alkyl it is refined to this application as alkylcarbonyl.

&Quot; Acyialkyl &quot; means a lignar monovalent hydrocarbon radical of one carbon atoms or a branched monovalent hydrocarbons radical of six carbons substituted by at least one, one or two, acyl group (s) as defined berein, metbylcarbonylmethyl, benzoyl, piperidine l-ylcarbonylniethyl or eihyl, and the like.

&Quot; AminocarbonylM means -CONRR'radical where R and R! are independently selected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cr hsterocycloalkylaIlcyl or R and R 'togeiher with the nitrogen atom to vrfiich they are attached to the background.

&Quot; Andnosulfonvl &quot; means -SO2NRR 'radical tvhere R and R' are independently selected from hydrogen, aryl, aryl, aralkyl, beteroaryl, heteroarahcvl, or heterocycloalkylalkyl or R and R 'to form a nitrogen atom to which they are attached form heterocycloamino as defined herein.

&Quot; Animal &quot; inclndes humane, non-huraanmannnals (eg, dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (eg, birds, and the like).

&Quot; Aromatic &quot; ibid., i.e., i.e., i.e., i.e., i.e., i.e., i.e., i. e.

&Quot; Aiyl &quot; containing a monocyclic or iused bicyclic ring assembly containing 6 to 10 ring carbon atoms, each ring being aromatic, e.g., phenyl or naphthyl.

&Quot; Aryloxy &quot; refer to a -O-R radical where R is as defined above, phenoxy, napthyloxy, and the like.

&Quot; AryloxycarbonyT refers to a -C (O) OR radical where R is aryl as defined above, phenyloxycarbonyl, naphthyloxycarbonyl, and the like. 8 &quot; Axalkyl &quot; reiers ίο a - (alkylene) -R radical v is as defined above, benzyl, phenethyl, and the like.

MAraIky] oxy &quot; refer to a -O-R radical where R is aralkyl as defined above, benzyloxy, phenethyloxy, and the like.

, Axalkyloxycarbonyl &quot; refer to a -C (O) OR radical where R is axalkyl as defined above, benzyloxycafbon.yl, pheneihyloxycafbonyl, and the like.

Bxamples include, but are not limited to, protein, recombinant and murine antibodies. , toxins, honnones, and the like, Biologicals are ciirrently available for the treatment of diseases such as cancer. rheumatoid anhritis, and hemophilia.

&Quot; Carboxy &quot; refers to -C (0) OH radical.

&Quot; CycloaIkyr &quot; refers to a mono valentine monocyclic ring containing fbree to eight ring carbon atoms, e.g., cyclopropyl, cydobuiyl, oyclopentyi, cyclohexyi, and the like.

&Quot; CycIoaBcylalkyr refers to a - (alkylene) -S. radical v / here R is cycloalkyl as denned above, cyclopropylmeihyl, cyclobutyiethyl, cycIobuiytnetbyl, and the like.

"CycloalkyloxycarbGiyr" refers to a -C (O) OR radical sulfurylcycloalkylcycloalkylcycloalkyl, cyclopentyIoxycaibonyl. and the like.

&Quot; Cycloalkylene &quot; refers to a divalent satorated monocyclic ring containing three to eight ring carbon atoms. For example, the instance v / i &quot; R3 & R4 together with the R & R * are attached to the main cycloaIky! Ene &quot; includes, but is not limited to, the follovring: Δ.

and the like.

&Quot; Disease &quot; special includes any unhealthy condition or anthropogenic condition, of such therapy. 9 9 EN 13669 “Derived” means a similar agent can be traced to.

[0053] "Deleterious immune response" means a response to a patient or cause disease in a patient. As an example, dosing apathetic vvith a murine antibody or a diagnostic agent that prevent cr interferev / ith ongoing treatments. The incidence of antibody formation versus pure murine monoclonals can exceed 70%. (see Khazaeli, B.B. et al., J.Mymmunother. 1994, 15, pp. 42-52; Dillman R. O. et al. Cancer Biother. 1994, 9, pp. 17-28; and Reinsberg, J. Hybrido? na. 1995,14, pp. 205-208). Additionally, there is a factor in the development of blood-clotting factors such as factor V3H. Though factor VHI is also a human protemic strain, as well as an endogenous factor in the endocrine system. Approxiiaately 29-33% of new patients will be producing antibodies and binders (see Lusher J.M. Semin Thromb Hemost. 2002.28 (3), pp. 273-276). Thess neutralizing antioxidants; (see Briet E et al. Adv. Exp. Med. Bio. 2001,489, pp. 89-S7). Anoleher immunogenic exampie is adenoviral vectors. Retroviral therapy remains expexitional and i-s of limited uti3ity. One reason is that a response to the same or similar viruses (see Yiping Yang et al. J.Virology. 1995, 69, pp. 2004-2015). This is a botanical genome. (See Hanne, Gahery-Segard, et al., J. of Virology, 1998, 72, pp. 2388-2397) suggesting that virai modifications will not be sufBcient to overcome this obstacle. This invention will provide a process for the treatment of adenoviral therapy. Another example of an immunogenic agent is botoxic agent Botox. Botulin toxin protein, is a source of Clostridium botulinum. As a therapeutic agent, it is used for the treatment of cystic dystonia in addition to cosmetic application. (See Birldein F. et al., Ann Neurol. 2002, 52, pp. 68-73 and Rollnik, J.D. et al., Nevrol Clin.

NaurophysioI. 2001,2001 (3), pp. 2-4). The "deleterious immune response" also encompasses diseases caused by a therapeutic agent. Response to therapy with recombinant human nonytliropoietin (EPO). Erythropoietin is nsed to stimulate the growth or red cell counts in patients who have undergone chemotherapy or dialysis. EPO and their own endogenous EPO ('ses CasadevaU, N. N. al., NEJM. 2002,346, pp. 469-475). They contract a disorder, pure red cell aplasia, in Gershon S. K., al., Al. NEJM, 2002,346, pp. 1584-1586). This complication ofEPO therapyis lethal if nntreated. Another specific example is the marinating antibody, OKT3 (a.k.a., Orthoclone), a monoclonal antibody directed towards CD-3. In clinical trials 20-40% of patients administered OKT3 produces antibodies versus the therapv. These antibodies, besides neutralizing the therapy, also stimulate a stronghost immune reaction. This is the Orthoclone ackags bay. Final example is ahuman antibody therapeuric. Humira® is an amonoclonal antibody directed against TNF and is used to treat rheumatoid arthritis patients. Wh.en. taken alone. ~ 12% of patients develop neutralizing antibodies. In additior, a small percentage of patients. The drug is also known as the 'Humira packaģe'.

Another example of a "deleterious iimnune response" is a host reaction to small molecule dmgs. It is knov / n to those shaves. Chemical structures will conjugate with host protein to stimulate immune recognition (cf. Ju. C. no. 2002. Currer.t Drug Metabolism 5, pp. 367-377 and Kimber I et al., 2002, Toxicologic Pathology 30, pp 54-58.) A proportion of these host reactions are IgG mediated. Specific "deleterious immune responses" that are IgG mediated include: hemolytic anemia, Steven-Johnson syndrome and drug induced Lupus.

&Quot; Halo &quot; refers to fluorine, chlorine, bromine or iodine.

&Quot; Haloalkyl &quot; for one to seven, &quot; halo &quot; atoms, as such. Haloalkyl includes monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl. 11 11 EN 13669 and the liks e.g. cMoromethyl, dicMoromethyl, difluoroethyl, trifluoromethyl, 2,2,2-trifluoro-phenyl, perfluoroacetyl, 2,2,2-irifluoro-l, l-dicororoethyl, and the like.

&Quot; Haloalkylene &quot; One of four hydrogen atoms in the alkylene chain is a fluorine atom (s).

[O05S] &quot; Ha3oalkoxy &quot; refers to, -OR radical where R is haloalkyl as defined above, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, and the liks.

&Quot; Heteroyl &quot; as a group of atoms, in one or two of the ring atom (s) is selected from nitrogen, oxygen or sulfirr, the remaining ring atoms being carbon. Representative heteroaryl rings include, but are not liraited to, pyirolyl, ihranyl, thienyl, oxazolyl. isoxazol, thiazolyl, imidazolyl, triazoyl, tetrazolyl, pyridinyl, pyrrolidinyl, pyrazinyl, pyrfdazinyl, indolyl, benzofuranyl, benzothiophenyl, benziroidazolyl, quinolinyl, isoquinoinyl, quinazolinyl, qninoxalinyl, pyrazolyl, and the like.

&Quot; ΗεΐεΓΟβχγΙοχ '/' refer to a -O-R radical v is heteroaxyl as defined above, fyria, pyridinvloxy, indolyloxy. and tbe like.

&Quot; Heteroaiyloxycarbony] ”refers to a -C (0) 0-R radical where R is heteroaxy! as defined above., &lt; 3iny! oxycarbony, pyriinidinyloxycarbonyl, and the like.

&Quot; Heteroaralkyl &quot; refers to a - (aylene) -R radical where R is heteroxyl as defined above, pyridinylmihy3,1- or 2-furanyl, inridazolylmethy3, and the like.

&Quot; Esieroaxalkyloxy &quot; refer to a -O-R radical v is H eeroaralkyl as defined above, pyridinyhneihyioxy, furanyethyoxy. and the like.

&Quot; Heteroaralkyloxycarbonyl &quot; refers to a -C (O) 0-R radical where R is heteroaralkyl as defined above, pyridinyhnefhyloxycarbonyl, pyrirrubinhnetliyloxycarbony3, and the like.

&Quot; Heterocycloalkyr to a saturated or paitHy unsaturated, mono or bicyclic radical of 4, 5 or 6 carbon ring atoms, or one, two, or three of the ring carbon atoms are replaced by a heteroatom selected from -N =, -N-, -O-, -S-, -SO-, or -S (0) z- and furiher vvherein one or two ring atoms are optional replaced by a keto (-CO-) group . The heterocycloalky] ring is optional for cycloalkyl, aryl or diethyl aryl 12 ring defined for example, but not limited to, iimdazo] idyl, moxypolyolinyl, thiomorpholyl, thiomorpholino-1-oxide, thiomipholino-1,1-dioxide, tetrahydrofranyl, tetrahydropyranyl, tetrahydrofiopyran, 1-oxo-tetrahydrothiopyranyl, 1,1-dioxotetratylpyranyl, indolinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrrolidinyl, qumuclidyl, 3I-dxhydroisoquinoliryl: dihydroindolyl, and the liks.

When the heterocycloalkyl group is at least one nitrogen ring it is refined to hereia, as well as a heterocycloalkyl group as defined above.

&Quot; Heterocyclylalkylene &quot; refers to a divalent heterocyclyl group, as defined in this application, eg, the instance of Tvhsrein R3 and R4 together with the cafe atom Rv and R4 are attached to the main heterocyclylalky :: includes, but is not limited to, the following :

in vvhich R is a substituent as defined in the Summary of the Invention, refers to a - (alkylene) -R radical or heterocycloalkyl as defined above, pyxrolidinylmethyl, tetrahydrouryllethyl, pyridinylmethylpiperidinylmethyl, and the like .

Heterocycloalkyloxycarbonyl &quot; refer to a -C (O) OR radical where R is heterocycloalkyl as defined above, pyridinyloxycaibonyl, pyrimidinylxycaxbonyl, and the like.

&Quot; Hydroxy &quot; meaos -OH radical. Unless indicated othenvise include protected derivatives; Benzyl and the like.

&Quot; Hydroxya] Kyl &quot; one of two carbon atoms or a branch of a carbon monoxide atomic nucleus. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl) -1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 44-hydroxybutyl, 2J3-dibydroxypropyl, 1- (hydroxymethyl) 42drydroxyethyl, 2,3-dihydroxy-butyl, 3,4-dihydroxy-butyl and 2 - (hydroxymethyl) 43-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1- (hydroxymetbyl) -2-bydroxyetbyl.

&Quot; Isomers &quot; mean compounds of Formula (s) having the same molecular fonnulae but different in nature or in the sequence of their atoms in space. Isomers that differ in the order of their atoms in space are teims &quot; stereoisomers &quot;. Stereoisomers that are not nairror images of one another are teimed &quot; diastereomers &quot; and stereoisomers that are nonsuperimposable mirror images are teimed &quot; enantiomers &quot; or sometimes &quot; optical isomers &quot;. The carbon atom bonded to four nonidentical substitutes is a "chiral oenter". The compound with one chiral center is the "racemic mixture". The compound that has more than one chiral center has 2n '] enantiomeric pairs, where is the number of chiral centers. Compounds vriih more than one center of the diastereomers, and a "diastereomeric mixture". When one chiral center is present a stereoisomer may be a chiral center. Attached to the chiral center. Enantiomers are defined by their chiral centers and described by Cahn, Ingold and Prelog. Methods for Stereochemical Nomenclature, Methods for Detection of Stereochemistry and Echinaceae (eg, "Advanced Organic Chemistiy", 4th ediiion, March, Jeny, John Wiley & Sons, New York, 1992) ). It is understood that the names are used in the formula (I) are meant to be encompassed by possible stereoisomers.

&Quot; Optional &quot; or &quot; optional &quot; or "may be" means the event or circumstance that may or may not occur; For example, one of the pbiasis is an aromatic ring in the form of a substitute or an alternative to the term. [0074] The present inventor also includes a derivative of a compound of Formula (3). The α-oxide derivative means the compound of Formula (I) in% hich anthrogen atom in an oxidized stats (i.e., N-O), e.g., pyxidine i-onds, and which possess the desired phaimacological activity.

&Quot; Paihology &quot; of the disease means the most important cause of disease.

&Quot; Phannu acceptable &quot; that use is a safe and effective way to reduce the risk of harm to the body. 7 use as well as humanphaimaceutical use.

&Quot;? Haimaceutical3y acceptable salts &quot; which are phaimaceuiically acceptable, as deSned above, and whičh. possess the desired phaimacological activity. Such salts include acid addition salts, hydrororic acid, sulic acid, nitric acid, phosphoric acid, and the liks; acetic acid, propionic acid. hexanoic acid, heptanGic acid, cvclopentanepropionic acid, glycolic acid, lactic acid, malic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (4-hydtoxybenzoyi) benzoic 2-ethanedisulfonic acid, 2-ethanedisulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 2-ethanedisulfonic acid, 2-ethanedisulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid , 4-methylbicyclo [2.2.2] oct-2-ene-1-caxboxylic acid, glucoheptonic acid, 4,4'-methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 3-phenyipropionic acid, trixnethylacetic acid, tertiary butylacetic acid, salicylic acid, glutaric acid, muconic acid and the like.

[0078] The present invention also relates to pharmacological agents for use in the manufacture of pharmaceutical compositions and pharmaceutical compositions. Acceptable inorganic bases include sodiumhydroxide, sodimn carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, A-metbylglucamine and the like. 15 15LV 13669 [0079] The present invention also includes prodrugs of a compound of Foramla (I). Prodrug means a compound that is convertible in vivo by metabolic means (eg by hydrolysis) to a compound of Formula (Γ). For example, an ester of a compound of Formula (Ϊ) containing a hydroxy group may be convertible by hydrclysis in vivo to the parent molecule. Altematively an ester of a compound of formula (Γ) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of Formula (I) containing a group of examples of acetates, citrates, lactates, tartrates, malonates, oxaates, salicvates, propionates, succines, fumarioses, maleates, meihylene-bis-Pb-hydroxynaphyose, gentisates, isethionates , di-p-toluoyltartrates, methylsulphonates, ethanesulpbonates, benzenesulphonates, p-ioluenesulphonates, cyclobexylsulphamates and quinates. Suitable esters of compounds of Formula (I) containing a carboxy group, described by Lemweber, F J. DrugMeiab. Res1987,18, page 379. Containing a group of compounds of the formula (Γ) containing a group of compounds described by Bundgaard et al., J. Msd. Chsm., 1989, 32, pp. 2503-2507, and include substifuted (aminomeihyl) benzoate, for example, dialkylamino-meihyibesoates and / or interrupted by an oxygen substitute nitrogen atom, eg an alkyiated nitrogen atom, more especialīy (moipholino-rnefhyl), e.g. 3- (4-methylpiperazinyl) benzoates, and (4-alkylpiperazin-1-yl) benzoates, e.g. 3- or 4- (4-alkylpiperazm-1-yl) benzoic acid.

&Quot; Protected derivatives &quot; means of componnds of Formula (Γ) in v / hich a reactive site or sites are blocksd vviih protecting groups. Protected derivatives of the Formula (s) are used as an inhibitor of the Formula (I) or in themselves may be active cathepsin S inhibitor. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 3rd edition, John Wiley &amp; Sons, Inc. 1999

&Quot; Therapeutically effective amount &quot; that is the amount of the disease; 16 16 LV13699 &quot; Treatment &quot; or &quot; treating &quot; .means any admimstration of a present invention: (1) inbibiting the disease that is experiencing or displaying the pathology or symptomology of the disease, or (3) ameliorating the disease. the pathology or symptomatology of the diseased (ie, reversing thepathology and / or symptomatology). &quot; Treatment &quot; or &quot; treating &quot; with respect to the use of a substance or a combination of the following: (1) (2) inhibiting the immune response in the animal that is experiencmg. or or symptomatology), or (3) ameliorating the immune response of the immune response (ie, orthodontic manifestations of the immune response). or reversing the paediatrics and / or symptomology of the antigenic peptides by MHC class ules molecules, reduced activation of T-cells and B-cells, and reduced lymphocyte response, and reduced lymphocyte response, and the lilce).

[0083] The expression "aromatic or ahcyclic ring in R5 is optionally substituted with one, two, or three Ra or selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo; selected from hydrogen, alky], haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one Rc selected from hydroxyaUryl, alkoxyalkyl, amino] alkyl, alkyl, heteroaryl, aralkyl, heteroaracryl, cycloalkyl, cycloalkylalkyl, ............. "in the deflection of R5 in the compound of Formula (1) means that the aromatic and alicyclic rings within the scope of '17' 17LV R5 wbether directly or indirectly attacbed (eg, R5 is cycloalkylalkyl, -cylene-X-R9 wherein X is as defined in the Invention and R9 is ary, aralkyl, etc.) Ra, or Rb and Rc, or Rc alone.

Preferred Embodirents I Certam compounds of Formula (I) witbin the broadest scope set fortb in the summaryof tbe Invention are preferred. Forexample: (A) R 1 is hydrogen or methvl, preferably bydrogen;

R 2 is cyclopropyl, 1-phenyleyl [-CH (C 1-5) CH 3] or orthoprazole-5-yl; prefsrably cyclopropyL

(1) Wiibm tbe above preferred group (A) and more preferred is R3 and is also alkyl, preferably mefhyl, ethyl, propyl or butyl. more at R4 is ethyl or propyl.

(2) Within a preferred group, more or less methyl, ethyl and R4 are al3cyl, most methyl, etbyl. propyl or butyl. more at R4 is xnethyl. Preferably, RJ and R4 are methyl.

Cycloalkylene, cyclopropylene, cyclopentylene, cyclopentylene, cyclopentylene , or cyclohexylene, more su cyc3opropylene.

(4) Witbin the above preferred group (A) and more than that, but they are attacbed fonu piperidin-4-yl substituted with nitrogen, with 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, or 1,1-dioxotetrahydrothiopyran-4-yl. 18 [0089] (i) Within the aboye preferred groups (A) and A (1 -4), and more preferably, R5 is haloa] Kyl, ·. preferably, difluoromethyl, trifmoromethyl, 2,2,2-trifluoroethyl, 1,1,2, ZA-pentyl-ethyl, 1,1,1,2,3,3,3,3-heptafluoropropyl and R7 andR8 are hydrogen.

(Ii) Within the above preferred groups (A) and A (l-4) and more preferred groups, there is no more than 5, halo, dif, difluoromethyl, trifluoromethyl, 2 , 2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R 7 is haloalkyl, preferably trifluoromethyl, 2,2,2-trifluoroethyl, or 1, 1,2,2,2-peniafiuoroethyl, and R 8 is also hydrogen.

(Iii) Within the above preferred groups (A) and -4 (1-4), more R6 is haIoalkyl, prsferably, dffluoromethvl, irinuoromethyĻ 2.2.2 -triiluorehvl, or 1,1,2,2,2-pentafluoroethyl R 'is also alkyl, preferably, methyl, ethyl, orpropyl, andRsis hydxogen.

(Iv) Within one of the preferred groups (A) and A (1 -4), there is a haloalkyl, par, oifluoromethyl, trif! UoromethyI, 2,2,2-trifluoroethyl, or 1,1,2,2,2-7-ol pentafluoroethyl, R is haloalkyl, trifluoromethynyl or 2,2,2-trifluoroethyl, and R is aryl optionally substituted with one, two, or thres Re. Preferably R8 is phenyi, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-dif3uorophenyi. More preferably, R6 and R7 are trifluoromethyl and R8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl.

(Iv) Within the above preferred groups (A) and A (1 -4), R5 is haloalkyl, preferred, difluoromethyl, triiloyl Qethyl, 2.2 , 2-Trifluoroethyl, or 1,1,2,2,3-pentafluoroethyl, R7 is aXkyl, preferably methyl or not, and R8 is aryl optionally substituted with one, TV / o, or three Re. Preferably R 8 is phenyi, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl. More, R6 is trifluoromethyl and R7 is methyl and R8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl . 19 19 LV 13669 (v) The above prefeued groups (A) and A (l-4) and more prefixed groups contained therein, are Rho is halo, alkyl, trifluoromethyl, difluoromethyl, 2,2,2-Trifluoroethyl, or 1,1,2,2,2-pentylhydroxy R7 is hydrogen, and R8 is aryl optionally substituted with one, two, or three Re. PxeferablyR8 is pbenyl, 4-fluorophenyl, 2.3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl. More, Rs is trifluoromethyl and R8 is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl, preferably 2,4 -difluorophenyl.

(Vi) Within the above prefeued groups (A) and A (l-4) and more preferred groups are therein a haloalkyl, preferably trifluromethy], 2.2, 2-Trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R 7 is ha] oylcyl, trifluoroethyl or 2,2,2-trifluorohexyl, and R 5 is heteroaryl optionally substituted Vvith one, two, or three Re. Preferably R8 is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl], furan-2-yl, pyridin-4-yl], pyridin-3-yl, pyridin-2 -yl, imidazol-5-ylpyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimidine-4-yl, pyridyl] n-4-yl, isoxazol-4-yl, imidazol-2-yl yl, [1,2,3] thadiazol-4-yl, imidazo-4-yl, pyrazol-4-yl, imidazol-2-yl pyrazol-4-yl, pyriol-2-yl, pyrr] -3-y, thiazol-4 -yl, thiazol-5-y! optionailv substituted vvitii one or two methyl.

(Vii) The above-mentioned groups (A) and A (1 -4) are more preferred groups, there are also trioluromethyl, 2,2,2- trifluoroethyl, or 1,1,1,2,2,2-pentafluoroethyl, R 7 is alkyl, preferably methyl, and R 8 is heteroaxyl optionally substituted with one, two, or three Re. Preferably R8 is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyxidine-4-yl, pyridin-3-yl, pyridin-2-yl , imidazol-5-yl, pyrrolidin-2-yl, pyrazia-2-yl, pyridazin-5-yl, pyrimidin-1-yl, pyrazin-4-yl, isoxazol-4-yl, imidazol-2-yl, [1.2. 3] thiadiazol-4-yl, imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, thiaxol-4-yl , thiazol-5-yl optional subsiituted -white one or two methyl.

(Viii) Within the above preferred groups (A) and A (1 -4) and more prefixed groups contained therein, R6 is haloalkyl, preferablj, trifluromethyl, 2,2,2 -tdfluoroethyl, or 1,1,1,2,2-pentylaminoethyl, R 7 is hydroxy, and and R 8 is heteroaryl optionally substituted w 1 h, two, or three Re. Preferably R8 is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl yl, imidazol-5-yl, pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimidine-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl, \ t [1.2.3] thiadiazol-4-yl, iridazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrol-2-yl, pyrr-3-yl, tbiazol-4 -yl, thia2ol-5-yl] y added νάΐα one or two methyl. {0098] (a) Within a short above prefened groups (A), A (1-4), A (i-viii) and A (1-4) (i-viii), and more rc is cycloalkylaIt is selected with one, two, or tbiee Ra and selected Srom alkyl or balo or an Rc selected aralkyl or heteroaroCyl, preferably 1-methylcyclopentylmethyl, l-methy] cyclohexylmethyl, 1 -. Methylcyclobutylmethyl, 1-methyl-3,3-difluorocyclobutylmethyl-1-methyl-4,4-difluoro-cyclohexylmethyl, 1-beimyl-cyclopropylmethyl, 1-thiazol-2-ylmethylcyclopropyl-3-yl, or 1-methyl-3,3-difluoro-cyclopenylmethyl. (B) Within the above preferred groups (A)} A (1-4), A (1-viii) and A (i-4) (i-viii), and more preferred groups contained therein, an sven more preferably 2J2-dimethylpropyl 3,3-dimethylpentyl, 2,2,3,3-tetramethylylbutyl.

(C) Within the above preferred groups (A), A (1-4), A (1-viii) and A (i-4) (i-viii), and more more 2,2-dichloroethyl, 2,2,3-trifluoro-propyl, 2,2-trifluoromethyl-phenyl, or 2,2,2-trifluoroethyl.

(D) Within the above preferred groups (A), A (1 -4), A (i-viii) and A (1 -4) (i-viii), and more preferred groups contained therein, an even more substituted with aryi, heteroaryl or heterocycloalkyl, 2,2-difluoro-3-phenylpropyl, 2,2-diyl chloro-3-tetrahydropyran-4-ylpropyl, 2,2- difluoro-3-moiphol-4-ylpropyl, 2,2-difluoro-3-pyrid-2-ylpropyl, 2,2-difluoro-3-pyridin-3-ylopropyl, or 2,2-dichloro-3-phenylpropyL

(E) Within the above preferred groups (A), A (1-4), A (i-viii) and A (1-4) (i-viii), and more preferred gronps contained therein, an even R5 is araUcyl optionally substituted wiib one, two, or three Ra or selected from aīkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or balo; or alternatively selected from bydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one Rc selected from 21 21LV 13669 hydroxyalkyl3 allcoxylayl, aminoalkyl, allyl, heteroaryl3 aralkyl3 heteroaralkyl, cycloalkyl3 cycloalkylalkyl , heterocycloa! 3cyl, heterocycloalkyla3kyl3 acyl3 aiyloxycaxbonyl, aiallcyloxycaxbonylJ heteroaryloxycarbonyl3 heteroaralkyloxycarbonyl3 heterocyclo alkyloxycarbonylJ aryloxy, heteroaryloxy, araDcyloxy, heteroaralkyloxy3 aminocarbonyl3 aminosulfonyl3 or -SCbR11 (where R11 is alkyl3 cycloalkyl, aryl3 heteroaiyl3 or heterocycloalkyl); and furtber wberein the aromatic or alicyclic ring in Rc is also selected from one3 two3 or thiee Rd is selected from alkyl3 haloalky3 ayxy, hydroxy3 haloalkoxy, orhalo. -4-y3methyl, naphth-1-ylmethyl-naphth-2-ylmethyl, 4-chlorobenzyl, 3-chlorobenzene, 4-fluorobenzyl, 2-phenyl; 4-Hydroxybenzyl, 2- (4-hydroxypbenzyl) -hydro-2,6-difluorobenzyl-3-biphenyl-3-ylmethyl-3-phenyl-propyl3 or 232-dimethyl-3-pbenzylpyridine. Prefersbly3 R3 is 2-cilorobenzyl3-3-chlorobenzyl3 or 4-ylorobenzyl.

(F) the above prefixed groups (A), A (1-4), A (i-viii) and A (14) (i-viii), group of componnds is that jar5 is heieroaraDcyl opiionally substituted v / itb one. two, or tbree Ra and selected from alkyl3 haloalkyl, a! lcoxy3 bydroxy3 haloaIkoxy3 cyano3 or halo: or optional wiih one or two Rb independenily selected from bydrogen3 alkyl. haloaIkyI3 alkoxy3 hydrcxy, halc3cxy, balo, carboxy, or alkoxycarbonyl and one Rc selected from bydroxyaliyl3a! aminoalkyl, aryl3 beteroar / l, aralkyl, heteroaiaīkyl3 cycloalkyl3 cycloaJky3aIkyl3 heterocycloallcyl3 heterocycloalkylalkyl3 acyl3 aiyloxycarbonyl3 aralkyloxycarbonyl3 heteroaiyloxycarbonyl, beteroaralkyloxycarbonyĻ ID = heteroaryloxy3 araIkyloxy3 beteroaxal3cyIoxy, aminocarbonyl3 arninosulfonyl3 or -SC &gt; 2RU (where R11 is aīkyl3 aiyl, heieroaryi, or heierocyc] oa] Kyi); and forthera tbe aromatic or alicyclic ring in Rc is optionally substituted witb one, two3 or tbree Rd selected from alkyl3 haloallcyl3 alkoxy, bydroxy, baloalkoxy, or halo. Preferably, R 5 is 2-bromothiophen-5-ylmethyl-3-pyridin-4-ylmethyl-3 or 2,2'-dimethyl-3-pyxidin-3-ylpropyl.

(G) Within the above preferred groups (A), A (14), A (i-viii) and A (1-4) (i-viii), more even more preferred R5 is - (alkylene) -S (O) 2-R9 vfhere R9 is also albyl, preferably R5 is methylsulfonylmethyl3 ethylsulfonylmethylpropyl-1-sulfonylmethyl], 2-methylpropylsulfonylmethyl3-2-methylsulfonylmethyl3 or 2-methylsulfonylphenyl. 22 (h) Within the above preferred groups (A), A (1-4), A (i-viii) and A (1-4) (i-viii), and more preferred groups contained therein, an even R5 is - (alkylene) -S (O) 2-R9 where R9 is axyl or aralkyl substituted with one or two radicals selected from alkyl3 haloalkyl-3-alkoxy3 hydroxy3 haloalhoxy3 cyano, orhalo; or alternatively vAtti one ortwo Rb is selected from hydrogen3 alkyl; haloalcyl3 alkoxy3 hydroxy, haloalkoxy3 halo, carboxy, or aHcoxycarbonyl and one Rc selected from hydroxyalkyl3axyxyalkylan anino]] cyl3 aryl, heteroaryl, aralkyl3 heteroaralkyl3cycloalkyl, cycloa]] cylallcyl3 heterocycloalkyl3 heterocycloalkylcycloalkyl acyl, aryloxycarbonyl3 aralkyloxycarbonyl, heteroarylcycloalkylcarbonyl, heteroarylcycloalkylcarbonyl, heteroarylcycloalkylcarbonyl. heteroaralkyloxycafonyl3 sylloxy, heteroaryloxy, arylcycloxy, beteroaralkyloxy3 aminocafbonyl, aminosulfonyl3 or SO2Rn (where R11 is alkyl3 aryl, heteroaryl, or heterocycloalkyl); and an aromatic or alicyclic ring in Rc is an optionallv substituted with one. two, or three Rd selected from alkyl3 haloalkyl; aIkoxy3 hydroxy, haloalkoxy, or halo. Preferably R3 is 2-difluoromethoxyphenyl-methanesulfonyImefhy], 2-phenylsulfonylethynyl-4-fluorophenyenetebenzenesulfonylmethyl3-4-fluorophenylmethylphenylmetharya-3-ylmethylphenyl-pipsrain-1-ylpheny3mefcanesulfonyline {h3'l; 2-Directhenylmethylphenylphenyl3 3-fluorophenyl &amp; anesulfGnyhmethyl. - (2-, 3-, or 4-fluorophenyl) sulfonylethyl.

(I) Within the above preferred groups (A). A (1-4). A (i-viii) and A (1-4) (i-viii) 3 are as follows: wherein R5 is - (alkylene) -S (O) 2-R9 where R9 is heteroaryl or heteroaxa3] cyl is optionally substituted with one or more of selected alkyl, haloalkyl, coxy, hydroxy3 haloalkoxy, cyano3 orhalo; orsubstituted with one ortho Rb, selected from hydrogen3 alkyl, haloalyl3 alkoxy, hydroxy3 halo] coxy3 halo3 carboxy3 or alkoxycarbonyl and one Rc selected from hydroxyaIkyl3 alkoxyalkylaminoalkyl, axyl3 heteroaryl3 aralkyl3 heteroaralky] 3cycloalkylcyclo [] cylaIkyl3 heterocycloalkyl3 heterocycloalkylcycloalkylcycloalkyl ) heteroarylxycaflonyL, heteroaralkyloxycarbonyl3-ylyloxy3 heteroaryloxy3 aralkyloxy3 heteroalkylxy, amixocarbonyl3 aminosulfonyl3 or -SO2Rn (where Ru is a] yl3 axyl, heteroaryl or heterocycloalkyl); selected from alkyl3 haloalkyl, alkoxy, 23 23 LV 13669 hydroxy3 haloakoxy3 or halo. Preferably R5 is pyrid-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl, pyridin-4-ylcyanenesulfonyl] -methyl) 3-dif] fluoromethoxypyridin-2-ylmethanesulfonylmethyl] -2 &lt; tb &gt; -difiuoromeihoxypyridiū-4-ylmetfranesulfonylmethyl3 pyiiirddin-2-ylmetlianesuIfoīiyliīiethylJ pyrimidin-5-ylmeffranesulfonytaiethyl3 3drifluoromethylpyridin42-ylmethanesulfonylmefhyl3 4-trifluoromethylpyridin-3-ylmethanesulfony3methyl3 3,5-dimethylisoxazol-4-ylmethanesuīfony] raeih'yl1 2rilrmroftuan-5-yl] meftanesulfonylmethyl3 2-methylihiazol- 4-y] methanesulfonylmethyl-3-pyridin-2-ylmethanesulfonylethyl] 2-pyridio-2-ylethanesulfonylmethyl-2-pyridin-3-ylmethylphenyl &gt; 2-Pyridin-4-ylhexan-sulfonylcyclyl-2-pyridin-3-yl-sulphonyl, 2-pyridin-4-ylsulfonyl-3-pyridin-3-ylsulfonyl-propyl, 1,3,5-1-triazol-2-ylmethanesulfonylmeflyl. 1,3,4-Phiadiazol-2-ylmethanesulfonylmethyl-oxazol-5-ylmethanesulfonyl] -methyl-3-thiazol-5-ylmethyl-e-sulfonylmethyl-3-methazol-4-ylmethyl] -phenylmyl.

(J) Within. the above preferred groups (A) 3A (1-4). A (i-Yiii) and A (1-4) (i-viii), and more preferred groups contained therein. more or less prefixed with a compound R2 is - (alkylene) -S (0) 2-R9 Tvhere R9 is heterocyclo] yl or heierocycloa3kylaiyu opuoiially substituted with one3 two. or tbree Rz is selected from slkyl3 haloaI3cy, alkoxy, hyaroxy3 ha! oalkoxy, cyano3 or balo; or opuonally substituted wnii one or iwo Rb is selected from hydrogen3 alkyl3 haloallcyl3 slkoxy3 hydroxy. haloa] i: oxy. halo. carboxy3 or alkoxycarbonyl and one R c selected from hydroxyalkyi3 alkoxyalkyl3 aminoaliyl3 aryl3 heteroaryl3 aralkyl3 heteroaryl] iyl3 cycloaHcyl3 cycloalkylaIkyl3 heierocycloaIkyl, heterocycloalkylaLk: yl3 acyl3 aiyloxycaibon'yl3 araHcyloxycarbonyl3 heiexoaryloxycarbonyi3 heieroaralkyloxycarbonyl, aiyloxy3heteroaryioxy, aralkyloxy3 beteroaralkyloxy3 aminocarbonyl3 arninosulfonyl, or -SO2R11 (where Ru is aliyl3 cycloaDcyl3 aryl3 heteroaiyl , or heterocycloalkyl); and fuither, or the alicyclic ring in Rc is optionally subsidized -with one, two3 or three Rd selected from alkyl3 haloalkyl 3 alkoxy3 hydroxy3 haloalkoxy, orchalo. Preferably3 R5 ispiperidin-1-ylsulfony] raethyl or piperidine-4-ylmethanesulfonylmethyl, the nitrogen atom in the piperidine ring is substituted with methyl3 ethyl3 acetyl, methylsu] phonyl, or aminosulfonyl, tetrahydroopyran-4-ylsulfonylmethyl-tetrahydropyran-4-ylsulfonylmethyl) 131 - dioxotetrahydrothiopyran-4-ylmethanesulfonylmethyl-3-morpholin-4-ylmethanesulfonyl-meflyl. 24 (k) Within the above preferred groups (A), A (1-4), A (i-viii) and A (1-4) (i-viii) 3 and more prefened groups contarned therein, an R5 is - (alkyene) -S '(O) 2-R9 where R9 is cycloalkylalkyl3 or R5 is cyclopropy] xylmethylsulfonylmethyl.

(1) Within the above preferred groups (A), A (1 -4), A (i-viu) and A (1 -4) (i-viii), and more preferred groups contained therein, R = is ethylsuIfonylmethyl3 2-inethylsulfonyl] yl] 2-methylpropylsulfonylmethyl, benzenesulfonylmethyl3-phenylsulfonylethyl3 naphih-2-y] meihanesulfonymethyl) biphenyl-2-y] methanes'aIlonyIinethy33bipheriyl-4-ylmethynylethylphenyl 2-pheny] methane lphenylmeihanesulionylmethyl 2-fluoro ^ henylmethanesulfonylmeihyl, 3- flnorophenyImethane-SĪilioriyIinethyI3 4-fluorophenylme &amp; anesulfoi'ylmsthyl3 2-cldorophenylmeflanesiilionylmeuiyl3 3-cWorophsnylmethanesulfony] inethyl3 4 ^ Horophenylmeihanesulfoiiylnieiiiyi3 2-Metho &gt;: ypheny3meihanesu] fonyImeft! yl3 4- meihoxyphenyImeihanesuIfonyImethyl3 2-trifuoromemoxypbenyIineihaiiesulfoiiylrncĪhyl) 3- tri-3-fluoromethoxyphenylmeihanesuIiolylmethyl] 3 4-irifiuorome &amp; cxypheny] mei3isulfonyhnethyl3 2-irifluoromethylph5nyl-methylene sulfate &amp; nylinethyl, 3 -MfluoromethyIpheny3rneihanesulfony! MeĪhy3. 4- irifluorome1kylphenyime &amp; ANESI! Rony3īnethy33 2-yl cyanbpheny3mεthaneΰlilfoτIy3metL · 3 ^ yancphenyMethanesultonylineihyl 2-bromophenyImethaiLesu3foiiyIinethyI3 2-methyIpheny] meihanesuIfonyimethyL 3-methylphenyImethanesulfony3methyl3 '4-methylphenyImethanesuIfony] iQeĪhyl3 2- (4-uifluoroniethoxy-benzeīiesulfonyl) ethyl-3 2- (3-trifluoromethoxybenzenesulfonyl) ethyl-3 2- (24-Fluoromethoxybenzenesulfonyl) -hydryl-2-difluoromethoxypheny] methanesulfonylmethyl-3-di-trifluoromethoxyphenyl-acethane-sulfonyl] -methyl-3-fluoro-fluoro-hydroxyphenylmethyl-benzenesulfonylmethyl-2- (4-difluoromethoxy-benzenesulfonyl) -ethyl 32- (2-difluoromethoxy-benzenesulfonyl) -ethyl- (2-difluoromethoxy-benzenesulfonyl) ethyl] 2- (3-difluoromethoxybenzenesulfonyl) ethyl- (2- (3-difluoromethoxybenzenesulfonyl) ethyl) 2- (3-difluoromethoxybenzenesulphonyl) ethyl ethyl3 SmMo [beta] -hydroxy-methanesulfonyl] -1,3-dimethylphenyknethanesulfonyl] methyl3, 3,5-bis-trifluoro] -ethylphenyl-methanesulfony] methyl3,25-difluoro-phenylmethanes] -phenylmethyl-2,6-difluoro-phenylmethanesulfonylmethyl; 233Afluorophenyimethanesulfonylmethyl-3,4-difluorophenylmethanesdfony] methyl3,24-difluorophenylmethylene sulfonyl and ethyl; 235- dichorophenyimeihanesulfoylmethyl &gt; 3J4-dichioropheny] rQethanesulfonylmethyl, 236-dichloropheny] methanesulfonylmethyl3-fluoro-3-methylpheny] meflmeu] methyl] nediyl) 25LVL 13669 4-Fluoro-2-1R fluoromethoxyphenylmethanesulfonylmethyl3-2-fluoro-6-fluorofluorophenylmethylene 2methanesulfonylmethy3- -1l-fluoromethylphenylmexanesulfonylHediyl3-2-fluoro-4-fluoro-fluoro-phenyl] -phenylmethane] -phenylmethyl-3-fluoro-5-trifluoromethyl-phenylmethanesulfonylmethyl-3-fluoro-3-trifluoromethyl-phenylmethanesulfonylmethyl] -2-cyano-5-trifluoromethyl-phenylmethylsulfonyl-5-trifluoromethylphenylmethylsulfonylmethyl-234,6-trifluoro-phenylmethyl-234,6-trifluoro-methyl] -2H-trifluoro-methyl] 5-Trifluorophenylmethanesulfonylethyl-3,333,4,4-fluorophenyl-methanesulfonylmethyl-23335-irifluorophenyImetbanesulfonylmethyl, 2,5,6-trifluoro-methylene-methyl] thienylphenylmethyl-3,4,5-

trimethoxyphenylmethanesulfonylethyl, pyridin-2-yl-pyridin-3-ylmethyl] -pyridin-3-ylmethanesulfoxylinethyl-3-pyrid-4-ylmethanesulfonyl} methyl) 2- (pyrim-2-ylsulfonyl) ethyl] 2- (pyridin-4-yl) phenyl) nonyl, oxypyridin-2-yl Methylene sulfonylsilylcyclohexylmerhanesulfanylmethyl3 cyclohexylmethanesulfonyl &amp; yl3 cyclopropylmethanesuccorylmethyl] Mophene-2-sulfonyl-3-methyl-5-cyano-formea-2-y] -phenylphenyl] -ethyl-3 or 335-dimethyl-isoxazol-4-ylmethanesulfonylmethyl]

(M) 3b (1-4), A (i-viii) and A (1-4) (i-viii). R5 is 1-ethoxycarbonylpiperidin-4-ylmethyl-31-methylpiperidin-4-ylmethyl-3-yl-pyrrolidin-4-yl-yl-3-pyrimidin-1-ylmethyl-piperidin-1-ylmethyl] -orpholin-4-ylmethyl; 2-Morpho-in-4-ylethyl-3 H-morphol-4-yl-benzyl-1-oxo-tinomol-4-ylmethyl. 1,3-dioxol-3-ylphenol-4-ylmethyl-tetralylothiopyran-4-ylmethyl-1-oxo-bromo-pyran-4-ylmethyl-1,3-dioxotetrahydro-3-yl-pyran-4-yl] -ethyl-3-methyl-piperazin-4-ylmethyl] -3-benzyloxymethyl-ethoxymethyl-3-isopropyl-oxethyl-3-piperidine -yl-ethyl3-2-pyrrolidin-1-ylmethyl-tert-butyloxymethyl] -imidazol-4-ylmethyl-indol-3-ylmethyl-3-indol-2-ylmethyl] -1-isisyl-quinazazol-4-ylmethyl-3-ethyl-4-methylpiperidine ( η 1 -methyl-3-indol-1-yl] methyl] -1-meflyl-piperidin-2-ylmethyl-2323-difluoro-3-thien-2-yl-methyl-3-pyridin-4-ylmethyl.

(N) Within the above preferred groups (A) 3 A (1 -4), A (i-viii) and A (1-4) (i-viii) 3 and more preferred groups coniained by R5is 335 -dimethyisoxazol-4-ylmethylene sulfonylmeihyi; 2-CF3methylIlien3-ene-ene-ene-3-ylmethyl-3,3-CF3-pyridin-2-ylmethanesulfonylmethyl-2-F-furan-5-yl-ethanesulfonyl-ibisyl-4-ylmethyl-1-thiazol-4-ylmethanesulfonylcarbonyl-tetraHydropyran-4-ylmethane-sulfone ] fony] methyl {1-ethylpiperidin-4-ylmetbanesulfonyl} ethyl] 2-oxo-tetrahydro-pyrimidin-4-ylmethane-sulfonylmethyl} -ethyl-26-2-oxo-piperidin-4-yl] -methanesulfonyl-ethyl} -1-acetyl-piperidin-4-ylmethanesulfonylmethyl, 1-methoxycarbonylpiperidine 1-methyl] -1-methylsulfonylpiperidin-4-ylidenesulfonylmethyl] -1-cyclopropylpiperid-4-ylidene-sulfonylmethyl] -1-acetyltetidin-3-ylmethanesulfonylmethyl-1-ethoxycarbonylmethylidene-3-yl] methanesulfonylmethyl, 1-methylsulfony] aza-3-ylmethylsulfony] azide-3-ylmethylsulfonyl] methyl] {1 H} 1-Ethyllazetidin-3-ylmethaneLesulfonylethyl 3-cyclopropyllazebdin-3-ylmethanesulfonylmethyl-foran-2-ylmethanesulfonylmethyl, difluoro- (4-yl-ethyl-ethyl) -ethylenesulfonyl] -methyl-difluoro (pyrazyl-2-y) -metha NesiiforiIlethyl) Difluoro- (2-difluoromethoxyphenyl) -methanesulfonylmethyl, 1-acetylpiperidin-4-ylsulfonylmethyl, 1-methoxycaibonylpiperid-4-ylsulfonylmethyl-5-cyclopropylpiperidin-4-ylsulfonyl, 2- (pyxidin-2-yl) &amp; anesidionyl-methyl3 - (Pyridin-3-yl) -phenylsulphonylmethyl, 2- (pyridin-4-yl) -hydsulfonylmethyl, 3- (pyridin-2-yl) -propylsulfoyl-ethyl-ethyl) 2.6-diyl-morphenenynexy] Jfonyl, [1.3.5] triaxm-2-yImeihanesalfony] [1.3.4] Ihiadia?; Ol-2-y] methanesulfonylmethyl-oxazol-5-ylmethoxy-sulfonylethyl yi, tbiazol-5-ylmethanesulfonylmethyl-4-fluoro-benzyl-3-methenesulfonyl] -ethyl-4-yl-carbonylphenyl-ethynylsulfonyl-4-piperazm-4-ylphenyl-4-piperazm-4-ylphenyl-3-piperazm-4-ylphenyl-3-methanesulfonylate; -fluoroind3-3-ymethylphenyldiethyl 3,436-difluoroindol-3-ylmethanesulfonylethylsulfanylindol-3-ylcetylsulfonyl ethyl3-fluoroindol-3-ylmethylsulfanyl]. 2- (5-Fluoro-diol-3-yl) -ethoxy-phenyl-ethyl-ethyl-2- (4,6-dichloro-dol-3-yl) -ethaneSilony] methyl. 2- (1-Melylindol-3-yl) ethanesylfil] inethyl 3 - 2- (4-fluoroindol-3-yl) ethane sulfonyl chloride 2-quinol-3-ylethynyl &gt; nylnethyl 3-qiolol-2-yl! y3methane-sulfonylacetyl 2- (isoquinolin-3-yl) ethanesulfonyl] -methyl-2,4-difluoro-pyridin-3-yl] -methanesulfonylmethyl, 334-di-fluoro-pyridid-4-yl] -isulfonyl-ethynyl-2- (2,4-diiloropyrid-3-yl) ) ethanesulfonylmethyl-2- (334-difluoro-pyridin-4-yl) -ethylenedioxy-phenyl-ethyl, fluoro (234-difluoro-pyridin-3-yl) -methaneses] -phenyl] -yl] -fluoro- (334-difluoro-pyridin-4-yl) -methanesulfonylmethyl-234-diCF3pyrid-3-yl -ylmetbanesulfonyl] methyl3,34-diCF3-pyridin-4-ylmethanesulfonyl-ethylethyl 2- (234-diCF3-pyrid-3-yl) -hexanesulfonylmethyl-2- (3,4-diCF3-pyridin-4-yl) -benzenesulfonylmethyl, -oro- (234-diCF3-pyridin-3-yl) ) methauesulfony] methyl, fluoro- (3,4-diCF3-pyridin-4-yl) methanesulfonylmethyl, 4-F-pyrid-3-ylmethanesilyl &gt; y] ethylene 3-F-pyridic-5-ynylsulfosyl-5-ylmethyl-F-pyridyl-5-ylmethylene ] fonylmetbyl, 2-F Pyridin-3-ylmethyl-xylene sulfonyl · αlethyl3-5-F-pyridin-2-ylmethyl-trifluoromethyl-4-F-pyridyl-2-ylmetbane-sulfonyl] -ediediyl-4-Fl-oxopyrid-3-ylmethylsulfonylmethyl, 3-Fl-oxopyridin-5-yl] me & ane-sulfonylmethyl, 2-Fl-oxopyridin-5-yl] methanesi] fonyIiethylJ 2-Fl-oxopyrid-3-ylmethane-sulfonylacetyl-5-Fl-27 27LV13669 oxop3ddin-2-ylmethanesulfonylmethyl3-Fl-oxopyridin-2-ylmethane -sulfonylmethyl-4-CF3-pyridin-2-ylmethanesulfonyl] methyl, 3-CF3-pyridin-5-ylmethylsulfonylmethyl-33-F-pyrid-2-yl] hexane-sulfonylmethyl-2-CF3-pyridin-3-yl] hexanylsulfonylmethyl 4-CF3-1-Oxopyridix-2-ylmethanesulfonylmethyl-3-CF3-1-oxopyridin-5-yl-acethanesulfonylmethyl-33-Fl-oxopyridin-2-ylamino-sulfonylmethyl-2-CF3-1-oxo-pyridin-3-ylmethanesulfonyl-phenyl] -5-CF3-1-oxopyridin-2-yl -y] inIlIlie'-fonylline-yl-32-CH3-pyddm-6-yl-thiophenesulfonylmethyl-3-CH3-pyrid-2-ylmethylene-sulfonylmethyl-4-CH3-pyridin-3-ylmethenesulfonyl-methyl-33-CH3-pyridin-4-ylmethylsulfonylmethylsulfonylmethylene 2 (2) -CH 3 -Pyridyl-6-yl) ethyl] phenylphenyl] inethyl 32- (3-CF 3 -pyrid-2-yl) ethanesine carbonylmethyl3 2- (4-CF 3-pyridin-3-yl) nonylsulfonylmethyl3 2- (3-0Ε3 ^^ ^ίη-4 ^ 1) ε & 3ηε5η1ίοηγ & αε &amp; γ13 2-C2Hj-Pyrid-6-ylmethylidene-phenyl-phenyl-3,3-C2H5-pyrid-2-yl] -methyl-methyl-4-C2H5-pyridazo-3-y] methanesulfony] methyl3-C2H5-pyridine -4-Chloro-enesulfonyl] - {Lyl3-2- (2-C2H5-pyridin-6-yl) ethanesulfonyl-ethyl} ethyl (2- (3-C2H5-pyridyl-2-yl) ethylsulfonylmethyl] -2- (4-C2H5-pyridyr-3-yl) n-isyl; ylJ 2- (3-C2H5-pyridm-4-yl) e-anisefonylmethyl-2- (2-CH3-pyridyl-3-yl) ethanesulfonylmethyl-2-CF3-pyridin-3-ylmethanesulfonyl-methyl-ethyl-2- (3-CF3-pyridinyl) 4-yl) etlianesulfoylmexyl. 3-CF 3 -Pyridin-4-ylmethanesulfonyl-1-yl-cimolm-3-ylmethane-sulfonylmethyl-32- (cyano-3-yl) -phenylsulfonylmethyl-3-phthalazin-1-yl] -thanes, alfoiiyImeĪh.yl. 2- (phenylazine-1-y)) sthanesulfonyimchihy3 2- (qidDoxalin-2-yI3 &amp; asesuuonyu3iethyi3 qumazoyl-2-y] mefhanesulfony] iDeihy] 3 - (quinaz; -2-y] indeneylphenyl] methyl3-2- ([13 8] iiapyridylidene-2-yl) ethanesulfony-3-methylphenyl] [1] 8-naphthynyl-3-yl &amp; anesulfony] ethyl-ethyl 2- ([l38] naphthyloxyl-3-yl) nonylsulfonyl] ethyl 3 C1-Pyridin-2-yl-ethanesulfonyl [nethyl3-4-Cl-pyridin-3-ylmethanesulfonylmethyl-3-Cl-pyridia-4-ylmethane] -phenyl] -ethyl-3-F-pyridin-2-yl] -carboxylate-3'-4-F-pyridin-3 -γΙπιεί1ΐ3ΐιε3ΐι1ίοην1 ^ ε ^ 13 3-F-pyiidin-4-ylmetiiaiLesulfonylinethyl3 isoq \ dnolm-4-yl] iīietIiaīiesuIfonyIiriethyl3 6-phenylpyiidm-2-ylm8thaiiesulfonyliaeŪiyl; 3 -phenylpyridin-2-yl] m8thaiiesulforiy] iaetJiyl3 4-pheuylpyxidiii-3-y ] methylidenesulfonylethyl-3-phenylpyTddm-4-y] methyleneLesilylphenyl] meLhyl3 2- (6-phenylpyridin-2-yl) ethanesulfonylmethyl-2- (3-phenylpyridin-2-yl) 8? 2-, 2- (4-phenylpyrid-3-yl) ethanesulfonylmethyl-32- (3-phenylpyxidyl-4-yl) 8-thiazenesulfonyl-6- (pyrid-2-yl) pyrid-2-ylmethanesulfonylmethyl-3- (pyridin-2-yl) pyrid-2-one Yi-8-liane-sulfonylacetyl ;, 4- (ργηάίη '· 2-γ1) ργπάία-3-γ] πιεώϊαε3η1β) ηγ1πιε ^ 13β- (pyridin-2-yl) pyrid-4-yl] methanesulfony-3-yl] -2- [6' (pyridyl) 2-yl) pyridin-2-yl] ethanesilylphenylethyl32- [3- (pyridin-2-yl) pyridin-2-yl] ethylidenesulfonylmephyl, 2- [4- (pyrid-2-yl) pyridin-3-yl] ethanesulfonylmethyl] - [3- (pyrid-2-y]) pyridyl-4-yl] non-propionylphenylmethyl-16- (pyridyl-3-yl) pyridin-2-ylmethylsulfonylmethyl-3- (pyridin-3-yl) pyrid-2-ylamino] sulfoyl] methyl 4- (Pyridin-3-yl) pyrid] -3-methylmethylsulfonyl-ethyl, 3- (pyrid-3-yl) pyridin-4-ylmethanesulfonyl] methylmethyl 2- [6- (pyridin-3-yl) pyridin-2-yl yl] ethax &gt; esylyl] ethylethyl 2- [3- (pyrid-3'-yl) pyridin-2-yl] ethanesulfonyl] indetyl] 2- [4- (pyrid-3-yl) pyridin-3-yl] ethyl] rDethylJ 2- [3- (Pyridin-3-yl) pyridyr-4-yl] eLhaiesulphonyl ethyl) 6- (pyridin-4-yl) pyrid-2-ylmethanesiloxylmethyl) 3- (pyridin-4-yl) pyridin-2-ylmethylene-3-sulfonylmethyl-4- (pyridin-4-yl) pyridin-3-ylmethanesulfonylethyl) 3- (pyridine -4-yl) pyddin-4-ylmethaneIfoEylmethyl ;, 2- [6- (pyridin-4-yl) pyridin-2-yl] -ethanesulfonyl] methyl) 2- [3- (pyridin-4-yl) pyTldin-2 -Yi] non-α-ionsulfonyloxyethyl) -2- (4-fluorophenyl) -4- (4) - [(4,4) -1,3-yl] n-2-sulfonyl] meiyl, 2- [3- (pyxidin-4-yl) pyriquin-4-yl] e1i ! ariesuliOEiyliiieiūyl3 2,2-dimethyl] cycIopropylmeihariesukl3BylmeiitylJbiphen-2-yl] rQethanesiilfoīiy] īnetliyI32-thiophen-2-ylphenylme £ haiiesulfoiiyImeihyi, 2-tiuszol-2-ylphsn} ^ linethaBssiilfonyliii5ihyl) 2 imazol-5-ylpheny] ineĪhaBesulionylmstĪiyl) 2- [l, 2.3] iMadiazol-5-ylphenylmefliane-sulfonylmethyl], 2-isoxazol-5-ylpheny] m5hane5uIfo3ykaethyl. 2- (1-Methylpyrazol-5-yl) phenyl-methanesulfonylmethyl, 2- [1,2,3] iriazol-5-y] phenylmethyl-qesulfori-3-yl] -2- [1.2.3] oxadiazole-5-ylpheny] meLhanesulfoylEDethyl3 2 - [(l , 2.3) triazol-5-yl] pentylmethyl-benzenesulfonylmethyl-2 - [(1.2.3) triazol-1-yl] phenylethanone] methyl, oxoGlo [5; 4-b] pyrid-2-ylmethane-sTiIf3iy] rQeyl: oxazolo [4,5-c] pyridin-2-ylmethanesulfonylmethylphenyl} oxazolo [4,5-b] pyrid-2-ylmethanesulfony] insylic acid 2-imidazol-5-yl] methanesulfony] -cyclohexylbenzimidazol-4-y] iaethaiiesulioiiy] metbyl: 3ίί-πηίά3ζο [435-b] pyridin-2-yl] -Bethanesulfoyl] -ethyl-3β-imidazo [4.5-c] pyridin-2-y] methanesulfo-ethyl-ethyl-3-CF3-32J-imidazo [41,5-b] Pyridin-2-ylmethylanesulfonyl] -phenyl} -3-CF3-3H-imidazo [435-c] pyridin-2-yl] -methylmethyl, 1-CF3-F-quinodazo [435-c] pyridin-2-y] methanesulfonylmethyl] yl! -CF3-Lif] iudazo [4,5-b] pyrid-2-ylmethanesulfonyl] -ethyl) thiazolo [534-b] pyridyl-2-ylmethanesulfonylmethyl-3-thiazolo [4,5-c] pyridyl-2-ylmethane] Mazolo [4,5-b] p yid-2-y] methanesulfony] inethyl, 5-CF3-thiazolo [534-b] pyrid-2-yl] methanesulfonylmethyl-34-CF3-thiazolo [435-c] pyridyl-2-ylmethylidene] methyl] -7-CF3-tbiazole [435] -b] pyridin-2-yl] methanesulfonylmethyl-3,3-CF3-yl-pyrrolo [2,3-b] pyridin-2-yl] methyl] -phenyl]] ethyl-33-CF3-1H-pyrrolo [332-c] pyridine-2 -methylbenzenesulfonyl-methyl, 3-CF3-yl-pyrrolo [332-b] pyrid-2-ylmethanesulfonylmethyl-3H-imidazo [1232-c] pyrimid-2-methanesulfonyl-ethyl] -8-CF34-transdiazo [1332-c] pymmdm-2-methanesulfonyl-phenyl] bmdazo [l32- a] Pyrimidine-2-inethoxyBesulfGnyImethyl3-CF3- 29 29 13139 Iirddazof1- [beta] -disil-2-ylmethane sulfonylmethyl] -imidazol-1-yl] thiazine-4-methanesulfonylmethyl-8-CF3-imidazo [l32-a] pyra-2-methanes'alfonylme { chylpyrazol [1,335-c] p-dinid-2-ene-3-ylmethyl-3,3-CF3-pyrazolo [1,3-c] pyrrolidine-2-ylmethanesulfonylmethyl] -4-CF3-pyrazolo [1,3-c] pyridinyl-2-ylmethylsulfonylmethyl, iiridazo [l32-d] ] [l &gt; 2,4] triazole-2-methariesulfonylmethyl, 3-CF 3 -ididazo [1,2-d] [1] 2.4] triazine-2-raethan esulfonymethyl3 [133] benzoxazol-2-yl] methylenedioxy-3-methyl) 5-F- [1,3] benzoxazol-2-ynnethanesulfonylmethyl- [1,333] benzoxazol-4-ylmethanesulfonyl-methyl-2-CF3- [1,3] benzoxazol-4-yl] -benzoxazol-4-yl} -methoxysulfanyl-ethyl] -ethylsulfanyl-ethyl] -ethylsulfanyl-ethyl] -ethylsulfanyl-ethyl] -hexylsulfanyl-ethyl] , [1333] benzoxa2,1-7-ylmethanesulfonylmethyl3,2-CF3- [1,333] benz2: oxazol-7-ylmethanesulfonylmethyl] [1332] benzoxazol-3-ylmethylenediamilyl] methyl] [1332] benzoxazol-4-ylmethanesulfonyl-5H-3-CF3 [l52] be] isoxazol-4-ylxenibaisilylphenyl] -ethyl-3,3-CF3- [12β-benzoxazol-4-ylmethanesulfonylmethyl] -6-CF3- [1332] benzoxazol-7-yl] imidazinyl} -ethyl] -6-CN- [1,2] nzoxazole- 7-y3methanesidylphenethyl 3-CF3- [132] benzoxa2; ol-7-ylmetbanesubonylmethyl3-5-F- [l32] benz; -7-Y3Eiefbanes] foil] ineyl31-CF3-f2J3] benzoxazol-7-ylamino] -phenyl] -silylsilyl 5-CF3- [233] imidazol-2-ol; CF3- [233] benzoxazol-4-yimeiGesulfonyIff benzo-thiazol-2-yl] methylsulfanyl-5-fluoro-benzothiazol-2-ylmethanesulfonylmethyl-benzenesulfonyl-4-fluoro-benzo [b] 2-CF3-benzo [b] iiazol-4-ylmethylsulfoyl] -methyl-benzothiazol-1-one yiirieihanesi] foiiylo2eiLyl3 2-CF3-benz-oylhiazol-7-ylmethylBesuconylmethyl-3 [132] benzothiazo-3-ylethylsulfony] methyl. [132] benzothiazol-4-ylmethanesulfony] MeLbyL 5-CF3- [1,2] bei Kothiazol-4-ylmetbaneneIdioxyuryl-3-CF3- [1,3] beezotazoM-ylmetbanesulfonylmethyl3-6-CF3- [13] benzothiazol-7-yloxy] sulfonylmethyl-6- CNT- [l32] benzoazol-7-yl-ethanesulfonylcyclohexyl-3-CF3- [1,332] benzothiazol-7-yl-thienyl] -Glycyl & y] 3 5-F- [1) 2] -ceacibiazol-3-ylbenzenesulfonylmethyl] [233] b8nothiazol-7-ylmethylsulfonylcyclyl-6-CF3- [2J3] benzo-benzyl-7-yl] thienylsulfonyl] methyl3-CF3- [233] benzothiazol-7-ylmeibanesulfonylmybyl3-5-CF3- [233] trifluoro-4-y] methaiiesu] 5'-CN- [2; 3] beDiazhiazol-4-ylmethoxy-sulfonylmethyl] -3'-CF3- [233] benzothiazol-4-ylmethyl-4-fluorophenyl-4'-CF3-2-CH3-thiazol-5-ylmethylate sulfonylmethyl-4-CF3-thiazole -5-y] methanesulfony] methyl3 4-CF3-2-p-ethyl-thiazol-5-ylmethylsulphonylmethyl, 5-CF3-2-CH3-thiazol-4-ylmethylene-1-phenyl-diethyl-5-CF3-thiazol-4-yl] -methanesulfonylmethyl-5-CF3- 2-Phenyl-thiazol-4-yl] -metbanesulfonylmethyl-5-CH3-thiazol-2-yl-bromoate; 3,5-CF 3 -Mazol-2-ylmethylglypholylmethyl-5-phenyl'-bdazol-2-ylmethanesulfonylmethyl-4-CH3-trifluoro-azimidin-2-ylmethyl-4-yl] -methyl-1, 4-GF3-ihiazol-2-yl] -ethylsulfoyl] -ethyl, 4- phenyl-thiazol-2-yl-ethylhexylsulfony] iaeyl :, 5-CH3-2- (pyridin-2-yl) - [133233] triazol-4-y] methanesulfonyImeflyl3 5-ΟΡ3-2- (ρ ^ (ίϊα-2 ^ 1) ) - [1 &gt; 2:, 3] 1ιΐ3ζο1-4 ^ 1ΰΐ6ΰΐ3η63υ1 & ^] ιχΐ6 ^ 1 :, 5-CF3-2- (4-methylsulfoylphenyl) - [(2S) 3] triazol-4-ylmethylsulfonylmethyl3 4.5 -dimethyl- [1,2,4] triazol-3-ylmethanesilyl] -pyridyl, 5-CF 3 -4-CH 3 - [1 3234] triazol-3-ylmethanesulfonylmethyl, 4-CH 3 -5-phenyl- [1 J 234] iriazol-3-ylmethyl sulfonylmethyl-5-CF 3 -4-cyclopropyl- [1; 234] iriazol-3-ylmethylxysulfoylmethyl; 235-Dimethyl- [1,2,4] triazol-3-ylmethanesulfonylmethyl3-5-CF3-2-CH3- [1332] triazol-3-ynethylsulfony] methyl) 2-CH3-5-phenyl- [l3234 ] triazol-3-yimethylsulfonyl-enylcyl, 2-cycl-propyl-5-pheyl- [1] -2J4] triazol-3-ylmethane-diphenylmethyl-5-C3r3-1-CH3- [133234] diazol-3-ylmethylene-sulfoylsulfanyl-1-CH3-5-phenyl - [133234] irisol-3-ylmethyl-phenylmethyl-5-CE3-1-yl] -1- [1,234] dio] -3-y] indole-4-yl] ethyl] -3-CH3- [1,334] o% adiazol-5 y] methanesulfonyl ethynyl 3-CF3- [133234] oxadiazol-5-yl] hexenyl] iothylethyl-3-phenyl- [1,234] oxadiazol-5-yl] -ethane-sulfonylmethyl-5-CH3- [133234] oxadia-2Bl-3-ylfluoroethylsulfanyl-5-CF3- [133234] oxadia2; o] -3-ylhydroxysulfonyl-5-phenyl] -234] oxadate-3-ene-ene-sulfonylmethyl-ethyl, 2-CH3- [1.3.4] cfiadi22ol-5-y3meflianesulfonylmethyl. 2-CF 3 - [1,3,4] cis-adiazol-5-yl] ethane-sulfonykaeihyl. 2-phenyl- [1,3,4] oxadiazol-5-yl] pyridinylmethyl-3-CH3- [1,2,2] thiadiazol-5-ylmethanesulfonylmethyl-3-CF3- [1,234] thiadiazol-5-ylmethanesulfonyl] -yl, 3-phsnyl4132; ] Hadiazol-5-yimeihydroxyphenylmethyl-3 5-CH3- [11,2,4] -Madiazol-3-ylmethyl-sulfonyl-ethyl] -5-CF3- [1232.4] tbiadiazol-3-ylmethylene-3-yl] ethylene, 5-phenyl- [1,334] Hadiazol-3- overethane sulfonylquetyl 3 2-CH 3 - [133.4] Madia 2 -ol-5-ylmethanesulfonyl-ethyl-ethyl 2- [F 3 - [1.3.4] thiadiazol-5-ylmethanesulfonyl] -acetyl-2-phenyl- [334] thiadiazol-5-ylmethane-sulfonyl-ethyl. difluoro-pyrrolidinylmethanesulfo-dynyl-3,333-diiloropyrrolidinyl-raethanesulfonylethylene &lt; / RTI &gt; 3-CF3-2 / -CK 3 -Pyrrol-2-ylideneLilofluoroethyl3,3-CN-N-CH3-pycol-2-ylmethanesulfonylmethyl-4-CF3-7 LCH3-pyrrol-2-ylmethylsulfamyl-ethylethyl 4- (1-CH3-l- hydroxyethyl) - N-CH 3 -pyrrole-2-ylidenesulfonylmethyl] -1,3-di-dihydro-pyrrol-2-ylamino-sulfonyl] -methyl-3-CF 3 -77-CH 3 -pyrrol-3-ylmethanesulfonyl-ethyl-4-CN-N-CH 3 -pyrrole-3 ylmethanesulfony] xaethyl3 4-CN-N- (33333-trifluoropropyl) -pyrrol-3-ylmethanesulfonylmethyl3,2-CF3-2V'-CH3-pynol-3-ylmethanesulpho-d]] ethyl] -2-CF3-N-phenyl-pyrrole-3-ylmethanone Sufonycethyl3 4-CF 3 -Pyrrol-2-ylmethylenedioxyphenylmethyl-4- (1-CH3-1-hydroxyethyl) -pyrrol-2-ylmethylsulfony] methyl3-3-CH 3 -pyrrol-2-ylmethanesulfonylmethyl-4-CF 3 -pyrrol-3-yl ylmethane-sulfonylmethyl-2-CF 3 -pyrrol-3-yl] methane &lt; / RTI &gt; -ylmethane-sulfonylmethyl-3-CF3-fta, -2-ylmethanesulfonylmethyl) 3-CN-4ur-2-ylmethanesulfonylmethyl3 3- CF3-Fux-4-y] Inanhanesulfonylmethyl-3-CN-urur-4-ylmethyl-phenylphenyl-2H-CF3-fur-3-ylmethanesulfonyl-Dethyl-3-CF3-Hazol-2-ylmethanesulfonylmethyl, 3-CN-thiazol-2-yl ylmethaneesulfonylmethyl3-CF3-thiazol-4-ylmethesulfonylmethyl, 3-CN-thiazol-4-ylmethanesulfonylmethyl ;, 2-CF3-thiazol-3-ylmethanesulfonylmethyl, Ν-ΟΗ3-3-ΟΡ3-1H-pyrazol-5-y] methanesulfonylmethyl) 7V'-CH3-3- (1-CH3-1-Lydroxyethyl) -1'-pyrazol-5-ylmethane-sulfonylmethyl3- (CH3-3-phenyl-1 # -p) Tazol-5-ylmethanesulfonylmethyl3 Y-CH3- • 3-CF3-Li-pyrazol-4-yl] QeI-eneylphenylethyl-3YY-CH3-4-CN-1F-pyiazol-3-ylmethyl-1'-ylmethyl-1H-pyridin-4-yl-pyrimidin-3-yl] IrleLh ^ 3les'αlforlyl · πaeίhyl5Λ, '- phenyF3-CF3-lir-pyrazol-4-ylmethyl-lysulfonylhydryl-phenyl-5-CF3-1H-pyrazol-4-ylmethanesulfonylmethyl (N-CH3-4-CF3-lifinidazole) 2-yl [Nethydrous] phenyl] inethyl3 [# -CH3-4- (1-CH3-1-hydroxyethyl) -1F-imidazol-2-yl] ethyl} -5] -IlonylLysilyl3 (N-CH3-4- phenyl-li-iinidflzol-2-ylmethane) sulfate Nyll3I-N-CB1-3-CF3-FF-pyrazol-4-ylmethylphenylethyl3 (N-CE3-2-CF3-LY-inFdazul-5-ylhyde) -sulfonylidenyl3 (N-CH3-2-phenyl-1F- uxdda2o-5-y] jnethsi &gt; e) -Silfony] Iisilyl3 (JV-CH3-5-CF3-Li-iiididazol-4-ylmethane) -Eu! (A'-Pylyl-5-CF3-ylimidazol-4-ylmethane) -sulfanylmethyl-4-CN- [12β] oxazol-5-ylmethanesulfonylmethyl-CN-3-phecy] - [1332] oxazol-5-ylmethanesulfonyl] -4 CN- [1232] OxazGl-3-yl-ethylsulfoyl-ethyl-ethyl] -4-CN-5-phenyl- [1 H] oxazol-3-ylmethyl-methyl-methyl &gt; 4-CN-Isolazol-5-ylethane-naphthalene-4-CN-3-phenyl-iso-thiazol-5-ynyl-quesulfoyl] -ethyl] -4-CN-isothiazol-3-ylmethylion-1-ylmethyl, 4-CN-5-phenyl-isothiazol-3-one y] Methylene sulfonylhydryl, 4-CF 3 - [1332] oxazol-5-ylmethanesilfonylmethyl-34-CF 3 -3-CH 3 - [13]] oxazol-5-ylmethynylsulfonylthio-3-CF 3 -3-pbenyl [13] oxa2; -5-ylmethanesulfonylmethyl-yl3-CF3- [1332] oxa7Gl-3-ybaeylamino] -propyl 4-CF3-5-CH3- [1332] oxazol-3-ylmethanesulfonylmethyl 4-CF3-5-phenyl- [1X-oxazol-3-ylmethanesulfonyl] .yl. 3-CF3- [1332] oxazol-4-ylmethanane-sulfonylmethyl] -5-CF3- [1332] oxazol-4-yl-ethanesulfonyl-methyl-34-CF3- [1,2] oxazol-5-ylmethyl] -phenylmethyl-4-CF3-3-CH3- [ 122.] oxazol-5-ylmethanesulfoylmethyl-4-CF3-3-pheyl- [1: &gt; 2] oxaol-5-yl] acetylsulfonylethyl-34-CF3- [1,3] oxazol-3-ylmethanesulfonylmethyl; 4-CF3-5-CH3 - [1332] oxazol-3-ylethynylsulfonylmethyl-4-CF3-5-pienyl- [1332] oxazol-3-ylmethanesulfonylmethyl-3-CF3- [1332] oxazol-4-ylmethanesulfonylmethyl3-5-CF3- [1,3] oxazol-4-ylidenesulfonylmethyl] -4 -CH3- [1,2] oxazol-5-ylmethanesulfonylmethyl-4-CH3-3-pibyl-ethyl [13] oxazol-5-ylmethanesulfonylmethyl-4-CH3- [132] oxazol-3-ylmethanesulfonylmethyl, 4-CH3-5-leadyl 32 [1.2] oxazol-3-ylmethane sulfonyl] methyl, 3-CH3- [1332] oxazol-4-ylmethanesulfonylmethyl-5-CHa-fl, 2] oxazol-4-ynylcanesulfonylmethyl] -4-CH3-isolazole-5 " -suIfcnyLinethyl; 4-CH3-3'-Phenyl-isothiazol-5-ylmethanesulfonyl-3-methyl-4-CH3-isothiazo-3-ylmethanesulfonyl] -methyl-5-CH3-5-phenyl-isothiazol-3-ylmethyl-4-phenylmethyl-3-CH-isothiazol-4-ylmethylsulfonylmethyl ester 5-CH3-isothiazol-4-yl] methanesulfonyl] acetyl-4-CF3-2-CH3- [1,3] oxazol-5-ylmethanesulfonyl] methyl3-CF3- [1,3] oxazol-5-ylmethanesulfonylmethyl 4 -CF3-2-phenyl- [1] 3-oxazol-5-yl] methanesulfonylmethyl &gt; 5-CF3-2-CH3-yl33] oxazol-4-ylmethanesulfonyl] alkyl-5-CF3- [1,333] oxazol-4-ylmethylsulfoyl] ethyl 5-CF3-2-p3-phenyl- [1,333] oxazol-4-ylmethylsulfoylmethyl-3-CH3- [1.3] Oxazol-2-ylmethanesulfonyl] Meyl3-5-CF3 - [33] ox2zol-2-yl] azanedronone &amp; yi 5,5-phenyl- [1] 3-oxazol-2-yn-ene-4-yl] -phenyl bromide &lt; / RTI &gt; 2-yuan &amp; novel meiyl3 4-C3r3- [153] oxazol-2-y] ene-phenyl-ethylidene-4-phsnyl- [1.3] oxazol-2-yl-hexane-alpha-4-yl-4-yl-2-ylmethylene] CFI-indol-2-ylmethylsulfonylmethyl. 3-CF3-A7-methyl-indol-2-yl-thienylphenylmethyl-5-fluoro-1F-methyl-indol-2-ylmethanesulfonyl] -ethyl-7H-enynyl-iiidol-3-ylmethanesulfonylphenyl. 2-CF 3 -indol-3-yl-4-fluoronylmethyl; 2-C3-N-N-methyl-molol-3-yl-cyano-carbonyl-3-yl-5'-fluoro-N'-methyl-benzol-3-ylmethane-8-carbonyl-5-CF3-F-methyl-mol-4-yl-ethanesulfonyl-diethyl-3-CN-2V'-methyl -dol-4-ynylacetylsulfonylmethylTol, 2-C3-N-methylmol-4-yl-ene-2-ylmethyl-ethyl, 3-CF3-N'-methyl-molol-4-ylmethyl] -methylsulfanyl-5-yl-6-CF3-Ar-methyl-indole -7-cyano-sulfonyl-ethynyl-6-CN-N-methyl-4-ol-7? -γ ^ οΙΙιβΐίβεαΙίοηγΙιιιείΙιγΙ, 3-CF3-Benzof4aii-2-ylmethylsulfonyl-ethyl-phenyl: 3-CN-benzofuraa-2-y] methanesulfonylidenibyl; -CF 3 -Benzo 2 -phen-3-ylmethanesonylphenyl 3 -ethyl, 2-CH 3 -benzoxybiphen-3-ylmethylsulfonylmethyl-35-F-benzofurai-3-yl] thienyl 3-trifluoromethyl, 5-CF 3 -beafophen-4-ylmethyl] phonylmethyl] T-butyl 5-CN-oxy-2-fluoro-4-yl] -ethianesilyl-phenylacetyl, 2-CF 3 -isisol-uran-4-ylmethylsulfo-3-methyl-3-CF 3 -benzofliran-4-ylmethanesulfonylmethyl-6-CF 3 -benxofuran-7-ylmethanesulfonyl} -ethyl-6-CN-benzoxofuran-6-CN-benxofuran- 7-y] -ethanesulfonylmethyl-3-CF3-butyloxy-2-ylmethyl-3-ene-3-yl-phenyl-3-ethyl-33-CF3-beta-thiophenyl-7-ylmethyl-sulphonylmethyl-benzothi-2-yl] -methanesulfonylmethyl- (3-CF3-benzothien-2-ylmetbane) -sulfonyl-methyl-3-sulfonylmethyl-3 (β-4? ] ιη842ΐΐ8) -5ΐΟ &amp; η73ιηοί1ΐ7ΐ, (5-F-Benzoethoxy-2-ylmethane) -sulfonylidene))) 20-ene-3-yl &amp; anesuconylmethyl3 (2-CF3-beuzothien-3-ylmethane) sulfonylmexyl (2-CH3-bisofen-bis) 3-yl-trifluoro [8] -sylphenylmethyl) 33 33LV13669 (5-fluoro-benzothien-4-ylmethane) -sulfonyl-ethyl (5-CF3-benzothi-4-yl) -methanone-sulfonylmethyl, (5-CN4-enisothien-4-yl) -carbonylmethyl-3 (2-CF3-benzoic acids) 4-ylmethane) -sulfonylmethyl3 (3-CF3-benzothien-4'-ylnexy) -sulphoyl] methyl) (6-CF3-benzothien-7-ylmethan) sulfonylmethyl (6-CN4ermothienY- ylmethane) -sulfonylmethyl3 (2-CF3-benzothien-7-ylidene) -sulfonylmethyl, (3-CF3-benzothi-7-ylmethane) -sulfonylmethyl-3H-methyl-benzylidenzol-2-yl-ethanesulfonylmethyl-3 (5-fluoro-JVr-methyl) benzimidazol-2-yl] methaae) sulfonylmethyl (77-methyl-indazol-3-ylmethane) -phenylmethyl, (5dluoro4 / mrethyldndazol4-ylmethyl) sulfonylmethy, (2-CF3-i7-methyl-benzimidazo-4) -yloxyhane) sulphoDy1DethylJ (2-CF3dV4nethylEenzimidazoyl-y] methylQe) sulfonylmethyl (7Ymehydryl 2 -methylmethane) -sulfonylmethyl3 (5-CF347mrethyl - mda2; ol-4-yImethane) -suIfonyLmetiiyI) (3-CF 3 Y / H ; e) -Sulionylmihyl, (6-CF3-N-mefhylmol-I-7-Me &amp; Me) -sulfonylacyl, (6-CN44neth-mdazolY-yImeth £ ne} -su3fonylethyl33r (3-CF344nethyldndaml-ylmethane) -suEonylmethyl. {0112] Within. and R6 is attached to (R) and to which R4 and R6 are atiached (S).

R5 and R6 are attached (R) and -vvhich R4 is attached (3).

(B) Another preferred compound of Formula (T) is that R3 is alkyl or methyl and is also alkyl, ethyl, propyl or butyl, more preferred R4 is methyl. Preferably, R3 and R4 are methyl, (C) Yet another preferred compound of Formula (I) R3 is R4 cyclropylene, cyclopropylene, or cyclobexylene. , more at cyclopro.pylene.

(D) Y and another group of compounds of Formula () is that rvhere together with the carbon atom which is atiached form piperidin-4-yl at the nitrogen atom with ethyl, 2, 2,2-trifluoroethyl or cyclopropyl, tetrahydrofuran-4-yl, tetrahydrothiopyran-4-yl, or 1,1'- (hoxotebah.hydrothiopyran-4-y).

(E) Yet another preferred compound of Formula (I) is that Rs is haloalkyl3-ene difluoromethyl, trifluoromethyl, 23232fluoroethyl3 or 13132,232-pentafluoroethyl and R7 and R8 are hydrogen. 34 (F) Yet the preferred group of compounds of Formula (I) that v / berein R6 is halocyclo, trifluoroethyl, trifluoromethyl / 1,2,2,2-trifluoroethyl, 1,1,2, \ t 2,2-pentafluoroethyl, R7 is halo, preferably, trifluoromethyl, 2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, andR8 arehydrogen.

(G) Yet an aberration of the group of compounds of Formula (T) that R6 is baoalkyl, preferably difluoromethyl, trifluoroethyl; 2,2,2-irifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R 7 is alkyl, preferably mefhyl, ethyl, or propyl, and R 8 are hydrogen.

(H) Ye anotber preferred group of Formula (I) that R6 is haloalkyl), 1,1,1,2,2,2-pentafluoroethyl or 1,1,1,2,3,3, 3-Hiafluoropropyl, R7 and R8 are hydrogen.

With the preferred groups (B) - (H), R 1, R 2, R 3, R 5, R 5 and R 5 ars as denned for group (A) above.

With the preferred groups (D) - (short), R1, R2, R &quot;. R4, andRs are as denned for group (A) abcve.

It sbould be noted that reference is to the above mentioned examples unless stated othenvise.

Representative of the compound of Formula (I) where R 'is by hydrogen, RS is trifluoromethyl and other groups are as defined in Table I below are:

i v 35

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GENERAL SYNTHETIC SCHEME

[0126] Compounds of this invention can be made by the methods depicted in the reaction schemes shovm below.

[0127] The starting material and reagents are as described in Aldiich Chemical Co., (Milwaukee, Wis.), Bachem (Toirance, Calif.), Or Sigma (St. Louis, Mo.). ) or are prepared by methods knovra to those skilled. Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chenustry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Cheroistiy (Jolm Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transfections (VCH Publishers Inc., 1989). These are some of the methods that are used in this article.

[0128] The starting material and the intermediates of the reaction may be isolated, and are not limited to filtration, distillation, crystallization, chromatography and the like. Such material may be characterized by conventional means, including physical constants and spectral data.

Undetermined to the temperature range from about -78 ° C to about 150 ° C, more or less from about 0 ° C to about 125 ° C and mostpreferably at about room ( or ambient) temperature, eg, about 20 ° C.

Amino-imino, carboxy groups, carboxyl groups, carboxylic acids, carboxylic acids, carboxylic acids, etc. Conventional protection groups may be used with standard practice, for examples see T.W. Greene and P.G., Wuts in &quot; Protective Groups in Organic Chemistrf &quot; Jolm Wiley and Sons, 1999.

Compounds of Formula (Γ) where R 1, R 2, R 3, R 4, R 5, R 6 and R 8 are as defined in the Invention and Reaction Scheme 1 helow. 45 45LV 13669

Schemel

Reaction of a ketone of formula 1 where R6 is a group of amino acids of formula 2 where R is a cafboxy protecting group, preferably a alkyl group, preferably melyl, aud R5 3) The reaction is as follows: TiCl3, magnesium sulfate, isopropyl trifluoroacetate, in the presence of a base such as diisopropylethylarmnes. pyridine, to give an imine. Cyanoborohydride is one of the most suitable agents for reducing the amount of alcohol in the body.

2-2,2-Trifluoromethylacetophenone and 2,2,2,4'-tetrafluoroacetophenone are commercially available. Others can be done by methods well known in the art. α-Amino esters of formula 2, PCT Applications PubHcationNos. WO 03075836, WO 00/55144, WO 01/19816, WO 02/20485, WO 03/029200, U.S. Provisional Application No. 60 / 422,337, U.S. PatentNo. 6,353,017B1, 6,492,662B1, 6,353,017 B1 and 6,525,036B1, 6,229,011B1, 6,610,700, the disclosuies of which are in their entirety in their entirety.

The hydrolysis of the ester group in compound 3 provides a compound of the compound 4. The hydrolysis of the ester group. For example, when the hydrolysis is can be out of the water, such as methanol, ethanol, and the like.

Compound 4 is then reacted with a hydroxycetoamide of formula 5 to give a compound of Fillula 6. The reaction is typically cairied with a coupling agent, benzotriazole-1-yloxytnpyrrolidinophosphoniuin hexafluorophosphate (PyBOP®). ), 4-enzotriazonyl-N, N, N'-triramethylmronium hezailuorophosphate (HBTU), O- (7-Azabenzotriazol-1-yl) -I] - (3'-tetramethyluronium hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl) -3-ethylcarbodine dihydrochloride ( EDC), or 1,3-dicyclohexyl-carbodiimide (DCC), optionalinthe-hydroxy-benzotriazole (HOBT), and abase. such as N, N-diisopropylethylamrne, txiethylaimne; iV-methylinorpho] me, and the like. The reaction is typically canied at 20 to 30 ° C, preferably at about 25 ° C, and requires 2 to 24 h to complete. Such as halogenated solvents (eg, methylene chloride, chlorofonn, and the.like), acetonitrile, NN-dimethylphenonide, ethereal solvents such as tetrahydrofuran, dioxane, and the like, [0135] The reaction typically requires 2 to 3 h to complete. The conditions utilized in this reaction depend on the active acid derivative. For example, if it is an acid chloride derivative of 4, the reaction is can be found in a suitable base (e.g., triethylamine, diisopropylethylacnine, pyridine, and the like). Suitable reaction solvents are polar organic solvents such as acetonitrile. N, N -dimethylphenamide, dichloromethane, or any suitable mixtuxes. Compounds of formula 5 in the PCT apphcation publication no. [0013] Oxidation of the hydroxyl group in compound 6 v / ith a suitable oxidizing agent such as provides® provides a compound of Formula (I).

Alteratively, the compounds of Formula (I) vhere R1, R2, R3, R4, R5, R6 and R5 are hydrogen as defined by the inoculation procedure. Reaction Scheme 2 below.

Scheme 2

7 8 9

11 4 (I) 10 47LV 13669

R5 is as defined in the Summary of the Invention. 10. Removal of the oxygen-protecting group 10. Removal of the oxygen protecting group 10. Removal of the oxygen protecting group 10. Formula (Γ) as described in Scherne 1 above. Suitable oxygen protecting groups and reaction conditions are described in Greene, T.W. and Wuts, P.G. M .; Protecting Groups in Organic Synthesis Sons, Inc. 1999

Altematively, compounds of Formula (I) where R 1, R 2, R 3, R 4, R 5, R 5 and R 8 are as defined in the Reaction Scheme 3 below.

Scheme 3

(I) Reaction of an amino acid compound of formula 2 is a 2- (1-hydroxy-2,2J2-) compound. trifluoroethylamino) acetate compound of formula 12. The reaction is can be found in the present invention.

Treatment of 12 with a compound of formula RSH where R8 is or heteroaryl under Friedel-Crafts reaction conditions or trialkylaluminum in toluene provides a compound of formula (Γ) as described above. [0140] Altemative compounds of Formula (Γ) where R1, R2, R3, R4, R5, R6 and R8 are as defined in the following Reaction Scheme 4 below.

Scheme 4

Where R 'is hydrogen or a carboxy protecting group and Rz is R5 or a precursor group (eg, allcylene-S-tīityl3 -a ^ lens-S-aljdene-heteroai '], and the like) to R5 group provides a compound of formula 15, The reaction is canied out in a suitable. ethanol, toluene, xylene, ethanol, benzene, toluene, xylene, and the like. Preferably, the organic base of triethylarmne, pyridine, N-methy3moxpholine, cohidine, diisopropyletliylamine, and the like. Preferahly, the inorganic base is cesi.um cafbonate, sodium carbonate, and the like. The reaction is as a molecular sieve. Preferably, the reaction is carried out at room temperature. 49 49 EN 13669 Compounds of formula 13 well known in the art. For example, a compound of formula 13 where R8 is also phenyl or 4-fluorophenyl and R6 is trifluoromethyl can be readily prepared from commercially available 2,2,2-trifluoroacetophenone or 2,2,2,41-tetrafluoroacetophenone respectively, by reducing the lithium alnminum hydride, and the like. The solvent used depends on the type of reducing agent. For example, when the reaction is carried out in an alcoholic, ethanol, and the like. When the lithium hydride is used as a reaction, it can be used as a solvent and as such, and the like. Reaction of 2,2,2-trifluoro-1-phenylethanol or 2,2,2-trifluoro-1- (4-fluorophenyl) ethanol with triflic anhydride or trifluoromethanesulfonyl chloride provides the desiied compound. Compounds of formula 13 where R7 and R8 are hydrogen and R6 is 1,1,2,2,2-pentafluoroethyl can be prepared from commercially available 2,2,3,3,3-pentafluoropropan-1-ol can as desciibed above.

OrBH3-DMS complex in the presence of a suitable catalyst such as (S) or (i?) - methyl CBS oxazaborolidine catalyst or (S) or (R) -ct, u-diphenyl-2-p &lt; g &gt; Compounds of Formula 14 • The Art.

[0143] Removal of the carboxy piotecting group from a compose of formula 15 where R 'is a protecting group of formula 16. For example, if R1 is alkyl, it is removed by means of an aqueous lithium hydroxide, sodium hydroxide, and the like. Additionally, if the group is compound 14 is a precursor group to R5, it can be converted to R5 prior or after the ester hydrolysis step. Compound 15 (where R 'is hydrogen) or 16 is then a derivative of formula 5 provides a compound of Formula ( Γ) when Rz is R5 or aprecursor compound to (Γ) vvhen Rz is a precursor group to RD. The substance may not be present at the same time as the substance is present in the body. vrith a halogenating agent such as iodine chloride, oxalyl chloride and reacted rvith compound 5. Altematively, the activated acid derivative is in situ by reacting compound 16 and 5 -yloxytrispyrrolidinophosphoniumhexafluorophosphate (PyBOP®), 0-Henzo-thiazol-1-yl-7α [7V'VV'J-tetramethyl-Uronium hexaftuorophosphate (HBTU), 0- (7-azabenzotriazolyl) ri, 1,3,3-triramrame-1-methyl-hexafluorophosphate ( HATU), 1- (3-Dimethylaininopropyl) -3-ethylcarbodiol hydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC), like in the presence of 1-hydroxybenzothiazole (HOBT), and in the presence of a base such as N-diisopropylethylamine, triethvlamine, N-meihylmoipholine, and the like. Such as halogenated organic solvents (e.g., methylene chloride, chloroform, and the like), acetonitrile, A, A-dimethylformamide, ethereal solvents such as tetrahydrofaran, dioxane, and the like. If R 'is a group R5, it is possible to convert from alkylene-S-alkylene-heteroarylalkylene-SO2-alkene-heteroaryl under. oxidation reaction conditions.

[0145] A compound of Formula (I). For exanaple: A compound of Formula (I) containing a hydroxy group may be prepared by alkylation / benzylation of an alkoxy / benzyloxy substituent; those containing an acid group, by hydrolysis of an ester group; and containing a cyano, a compound of Formula (I) containing a cyano group containing a hydrolysis of the cyano group. The carboxy group, in tum, can be converted to an ester group.

A compound of Formula (I) can be used as a base for a compound of the invention. inorganic οι organic acid. Altematively, apharm-like base of a compound of the formula (s) can be prepared by reacting to a compound v. Inorganic and organic acids and bases are suitable for use in the preparation of compounds of formula (I). Altematively, the salt foims of the formula (Γ) can be prepared using the orthogonal material or intermediates.

[0148] The free acid or free base of the formula (Γ) For example, a compound of Formula (I) is an acid addition salt form (e.g., amonmonium hydroxide solution, sodium hydroxide, and ihe like). A compound of Formula (Γ) in a base addition salt form is suitable for treating with a suitable acid (e.g., hydrochloric acid, etc).

[0149] The N-oxides of compounds of Formula (I) EXample, n-oxides can be prepared by treating an unoxidized form of the compound of Formula (I) with an oxidizing agent (eg, trifluoroperacetic acid, piacleic acid, perbenzoic acid, peraceiic acid,? / A-chloroperoxybenzoic add, or the like) in a suitable inert organic solvent (eg, halogenated hydrocarbon such as dichloromefliane) at approximate! 0 ° C. Altemaiively, the A-oxides of the Formula (I) can be prepared from- the N-oxide of an appropriate starting material.

Compounds of Formula (Γ) in unoxidized form can be prepared by a reducing agent (eg, sulfirr, sulfur dioxide, txiphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus tricMoride) , tribromide, or the like) in a suitable inert organic solvent (eg, acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 ° C. ] 0151] Prodrag of the compounds of Formula (I), for further details see Sanlnier et al. (1994), Bioorganic and Medical Chemislry Letters, Vol. 4, 1985). For example, with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloride, n-nitrophenyl carbonate, or the like).

[0152] Protected derivatives of the compounds of Formula (Γ) can be made by means of the art of skill in the art. The detailed description of the technics.es applicable to the creation of a group of children and their removal can be found in T.W. Greene, Protecting Groups in Organic Synihesis, 3rd edition, John Wiley &amp; Sons, Inc. 1999

[0153] Compounds of the present invention may be in the form of convents or in the process of the invention, as solvates (e.g., hydrates). Hydrates of thepresent invention may be made by means of organic solvents such as dioxin, tetrahydxoftyran or methylanol.

Compounds of Formula (I) can be used in the preparation of the compounds of the invention. &quot; Ϋ / ΜΙε resolution of enantiomers canbe out using covalent diasteromeric derivatives of Formula (I), dissociable complexes areprefeired (e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (eg, melting points, boiling points, solubilities, reactivity, etc.). The diastereomers can be separated by solving in solubility. The optically pure enantiomer is then recovered, along with the resolving agent. A more detailed.description of the stereochemistry of a racemic mixture can be found in Jean Jacques Andre Collet, Enantiomers, Racemates and Resoils, John Wiley. &Amp; Sons, Inc., (1981).

Preparation of Biological Agent [0155] Practices of Biological Agents are us ^ d. Methods for preparing the biology are well discussedαιον / η in the art as discussed below.

Monoclonal antibodies can be prepared using standard techniques such as the method of Kobler and Mlstein, Nature 1975, 256: 495, or as described by Buck et al. 1982, In Vitro 18: 377. Typically, a mouse or rat is immunized with the MenB. the spleen cell may be screened (after removal of the non-specylic adherent cell) by applying a cell suspension. B-cells, expressing membrane-bound immunoglobulin specific for the antigen, binding to the plate, 53 53 EN 13669 the rest of the suspension. Resulting B-cells, or ali-dissociated spleen cells, are then induced to a hybrid myeloma pathway to fon hybridomas. Representative muiiae myelora lines for use in the hybridizations include those available from the American Type Cultare Collection (ATCC).

[0157] Chimeric antibodies of the human and non-human amino acid sequences may be derived from the mouse (Winter et al. Nature 1991 349: 293; Lobuglio et al. Proc. Nat. Sci. USA 1989 86: 4220, Shaw et al J. Immunol 1987 138: 4534, and Brown et al., CaneerP.es 1987 47: 3577; Riechmann et al. Nature 1988 332: 323; Verhoeyen et al. Science 1988 239: 1534; and Jones et al. Nature 1986 321: 522; EP Publication No. 519, 596, published Dec. 23, 1992; and UX Patent Publication No. GB 2,276,169, published Sep. 21, 1994). . Antibody molecule fragments, e.g., F (ab ') 2, FV, and sFv molecules, that are capable of exhibiting irrelevant properties. Inbar et al. Proc. Nat. Acad. Sci. USA 1972 69: 2659; 'Hochman et al. Biochem. 1976, 15: 2706; Ehrlich et al. Biochem. 1980 19: 4091; Huston et al. Proc. Nat. Acad. Sci. USA 1988 85 (16): 5879; and U.S. Pat. Well. 5,091,513 and 5,132,405, and U.S. Pat. No. 4,946,778.

[0159] In vitro-display system can be used in vitro. Saiii, et al. Nature 1986 324: 163; Scharf et al. Science 1986 233: 1076; U.S. Pat. Well. 4,683,195 and 4,683,202; Yang et al. J. Mol. Biol. 1995 254: 392; Barbas, et al. Methods: Comp. Meth Enzymol. 1995 8:94; Barbas, et al. Proc. Nati. Acad. Sci. USA 1991 88: 7978.

[0160] The coding sequences for the heavy and light chain portions of the Fab molecules selected from the phage display library can be isolated or synthesized. Any suitable expression system, including, for example, bacterial, yeast, insect, amphibian and mammalian systems. Expression systems in bacteria include those described in Chang et al. Nature 1978 275: 615, Goeddel et al. Nature 1979 281: 544, Goeddel et al. NucleicAcids Res. 1980 8: 4057, European Application No. EP 36,776, U.S. Pat. Pat. No. 4,551,433 to de Boo et al. Proc. Nati. Acad. Sci. USA 1983 80: 21-25, and Siebenlist et al. Cell 1980 20: 269. 'Expression systems in yeast include those described in Hinnen et al. Proc. Nati. Acad. Sci. USA 1978 75: 1929, Ito et al. J Bacterial 1983 153: 163, Kurtz et al. Mol. Great. Biol. 1986 6: 142, Kunze et al. J. Basic Microbiol. 1985 25: 141, Gleeson et al. J. Gen. Microbiol 1986 54 132: 3459, Roggenkamp et al. Mol. Gen. Genet. 1986 202: 302, Das et al. J. Bacteriol. 1984, 158: 1165, De Louvencourt et al. J. Bacteriol. 1983, 154: 737, Van den Berg et al. Bio / Technology 1990 8: 135, Kunze et al. J. Basic Microbiol. 1985 25: 141, Cregg et al. Mol. Celi. Biol. 1985 5: 3376, U.S. Pat. Pat. Well. 4,837,148 and 4,929,555, Beach et al. Nature 1981 300: 706, Davidow et al. Curr. Genet. 1985 10: 380, Gaillard et al. Curr. Genet. 1985 10:49, Ballance et al. Biochem. Biophys. Res. Commun. 1983, 112: 284-289, TiTbum et al. Gene 1983 26: 205-221, Yelton et al. Proc. Nati Ācad. Sci. USA 1984 81: 1470-1474, ICel] y et al EMBOJ. 19.85.4: 475479; European Application No. BP 244,234, and Intemational Publication No. WO 91/00357.

Expiession of heterologous genes in iasects can be accomplished as described inU.S. Pat. No. · 4,745,051, European Application Well. EP 127,839 and EP 155,476, Vlak et al. J. Gen. Virol. 1988 69: 765-776, Miller et al. Ann. Rev. Microbiol. 1988 42: 177, Carbonell et al. Gene 1988 73: 409, Maeda et al. Nature 1985 315: 592-594, Lebacq-Verheyden et al. Great. Biol. 1988 8: 3129, Smiih et al. Proc. Nati. Acad. Sci. USA 1985 82: 8404, Miyajima et al Gene 1987 58: 273, and Martin no. DNA 1988 7:99. Numerous baculoviral sirains and variant and corresponoing permissive insect hosi cels from tosts are described in Luclcow et al.

Bio / Technology 1988 6: 47-55, Miller et al. GENETICENG1NEER1NG, Setlow, J. K. et al. eds., Vol. 8, Plenum Publishing, p. 1986 277-279, and Maeda et al Nature 1985 315: 592-594.

[0163] Mammalian expression can be accomplished as described in Dijkema et al. EMBO J. 1985 4: 761, Gonna et al. Proc. Nati Ācad. Sci. USA 1982 79: 6777, Boshart et al. Cell 1985 41: 52l, and U.S. Pat. No. 4,399,216. Other features of mammalian expression can be facilitated as described in Hana et al Meth. Enz. 1979, 58:44, Barnes et al. Outside. Biochem. 1980 102: 255, U.S. Even Well. 4,767,704,4,657,866, 4,921,162, 4,560,655 and Reissued U.S. Pat. No. RE 30,985, and in Intemational Publication Well. WO 90/103430, WO 87/00195.

[0164] The production of recombinant adenoviral vectors are described in U.S. Pat. No. 6,485,958.

[0165] Botulinum toxin type A and a cultivation of Closiridium botulinum in a herb and harvesting and purifying tbe feimented mbcture initing with knovrn procedures.

[0166] Any of the above-described protein production metlods can be used to provide the biological. 55 55LV 13669

Pharmacologist and Utilitv [0167] The compounds of the invention are selective inhibitors of cysteine proteases such as cathepsin S, K, B, and, in particular, cathepsin S, and. juvenile onset diabetes, psoriasis, multiple sclerosis, pemphigus vulgaris, Gravēs' disease, myasthera ditch, systemic lupus erythematosus, rhemnoidoid arthritis and Hashimoto's thyroidoid, allergic disorders, including but not limited to, organ transplants or tissue grafis and endomehiosis.

Cathepsin S is also implicated in disorders involving extensive elastolysis, such as chronic obstructive pulmonary disease (eg, emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, and cardiovascular disease such as plaque rupture and atheroma. implicated in fibril formation and, therefore, inhibitor of cathepsms.

The cysteine protease inhibition activities of the formula (I) can be deteimined by methods known in the art. Suitable in vitro assays for measuring protease activity and inhibition by compounds are known. Typically, the assay measures a peptide-based substrate. Details of assays for measuring protease inhibition activity are set forih in Biological Examples 1-5, infra.

Administration and Phamaceutical Compositions [0170] In general, the compounds of Formula (I) will be administered in a therapeutic manner. The 1herapeutically effective amount may be varied according to the severity of the disease. About 100 micrograms per kilogram body weight (pg / kg) per day to about 100 milligrams per kilogram body weight (mg / kg) per day, typically firom about 100 pg / kg / day to about 10mg / kg / day. Therefore, the therapeutically effective amount for an 80 kg / day to about 8 g / day human patient may range from about 1 mg / day to about 800 mg / day. In general, one of the ordinary skill in the art, is a method of treating a disease.

Oral, systemic (e.g., transdemial, intranasal, or suppository) or parenteral (e.g., iniramuscular, intravenous or subcutaneous) compounds. Compositions can take the fonn of tablets, capsules, semisolids, powders, sustained release fommlations, solutions, suspensions, elbdrs, spray, or any other form of formula (I) in combination v / ith at least one phaxm v acoeptable excipient. Acceptable excipients are non-toxic. Such excipient may be in any solid, liquid, semisolid or, in the case of an aerosol composition, is an alternative to one of the skill in the art.

Solid phannaceutical excipients include starch, cellulose, talc, glucose, lactose, .sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycol, propylene glycol and various oils including those of petroleum. animal, vegetable.or synthetic origin (eg, peanut oil, soybean oil, mineral oil, sesame oil, and the like). Prefened liquid carriers, especially forinjectable solutions, include water, saline, aqueous dextrose and glycols.

The amount of a compound of Fomrula (I) in the composition may vary according to the nature of the unit dosage. In general, a composition of a compound of formula (I) for treating a disease will be from 0.01% w to 90% w, preferably 5% w to 50% w, of active ingredient with the remainder being the excipient or excipients. Preferably, a single unit dosage form may be used for the purpose of the present invention. Representative physiological formulations containing a compound of Formula (Γ) are described below. 57 57LV 13669

Examples [0174] The present invention is further exemplified by reference to the invention.

Reference A

Synthesis of trifluoromethanesulfonic acid 2,2,2-trifluoro-1- (4-fluorophenyl) ethyl ester

Step 1

To a solution of 2,2,2,4'-tetrafluoroacetophenone (10 g, 52.1 mmol) in methanol (50 mL) was added NaBiL (0.98 g, 26.5 mmol) at 0 ° C. After drawing at 25 ° C for 2 h, reaction mixtuxe or quenched by adding 1N HCl (100 mL) and then extracted with ethyl ethe. The ether extract was washed with brine, and concentrated to give 2,2,2-irylthio-1- (4-fluorophenyl) ethanol (11.32 g) which was nsed in next step without further information. .

Step 2

NaH (640 mg, 16nol, 60% in mineral oil) was washed twice withhexane (20 mL) and then suspended in diethyl ether (20 mL). A solution of 2,2,2-trifluoro-1- (4-fluorophenyl) ethanol (1.94 g, 10 mmol) in diethyl ether (10 mL) was added at 0 ° C. After stining for 2 h at room a solution of trifluoromethanesulfonyl chloride (1.68 g, 10 mmol) in diethyl ether (10 mL) was added. After 2 h, the reaction mixture was quenched by a solution of NaHCO 3 and the product was extracted with diethyl ether. 2,2,2-Trifluoro-1- (4-fluorophenyl) ethyl ester (3.3 g). 58

Reference B

Synthesis of 2,2,2-trifluoro-1 (R) - (4-fluorophenyl) ethanol QF3

To -78 [deg.] C. toluene (25 mL) / dichloroethane (25 mL) solution of 2,2,2,4'-tetrafluoroacetophenone (2.5 g, 13.01 mmol) and 1M dichloromethane CBS oxazaborolidine catalyst (1.3 g). mL, 1.3 mmol) was added fieshly distilled catecholborane (1.66 mL, 15.62 mmol). The reaction mixture was maintained at -7 8 ° C for 16 h at 4N HCl (5 mL in dioxane). The reaction mixture was diluted with ethyl acetate and washed with a saturated brine solution. The organic layer was. dried over magesium sulfate, filtered and concentrated to provide a solid. The solid was suspenaed in hexanes and filtered off. The hexanes filirate containing the desired product as colorless oil (2.2g, 87% yield). Thermation of enantiomers was detected 95: 5 by chiral HPLC (Chiralcel OD column, 95 hexanes: 5 isopropanol mobile phass. Ret. Time major product 6.757 min. Ret. Time minor isomer 8.274 min.).

Reference D

Synthesis of 2 (R) - [2,2,2-Trifluoro-1 (5) - (4-fluorophenyl) ethylarmno] -3-tritylsulfanylpropionic acid

A slurry of S-trityl-L-cysteine (4.86 g, 13.37 mmol) in dichloromethane (97 mL, 20 mL / g AA) was added diisopropylethylamine (9.32 mL, 53.48 mmol) followedby a solution of trifluoromethanesulfonic acid 2,2,2-trifluoro-1 (R5) -phenylethyl ester (5.32 g, 16.04 mmol) (major enantiomer (S), 90 ee) in dichloromethane (15 mL) via syringe ali at once. After 19 h, the reaction mbcture was concentrated on the rotovap to give an oil. Diethyl noher was HCl and brine. The organic layer was 59 59LV 13669 dried over MgSO 4 filtered, and concentrated. 2 x 2-trifluoro-1 (AS) '(4-fluorophenyl) ethynyl] -3-tritylIfarLyl -propionic acid (6 g) (major diastereomer (R, S), 90 de) as an oil / foam.

Reference E

Synthesis of 2- (1-Aminocyclopropyl) -1V'-cyclopropy-2-hydroxyacetamide

Stepi 1-Arnocyclopropanecarbonitrile chloiohydrate (6.1 g3 51.4 mmol) was refluxed in 6N Hydrochloric Acid (500 mL) for 7 h and then concentrated to yield the title compound: carboxylic acid chlorohydrate. used in the next step ithout further purification.

Step 2 A solution of 1-aminocyclopropanecarboxylic acid chlorohydrate (3.6 g, 26.2 mmol) in MeOH (100 mL) containing potassium carhonate (4.0 g 3 28.94 mmol) was stirred at room temperature for 48 h. After filtration. MeOH v / as removed under reduced pressure to yield 1-aminocyclopropanecarboxylic acid (2.64 g) v / hich was used in the next step without further purification.

Step 3 [0180] 1-Aminocyclopropanecarboxylic acid (2.64 g, 26.1 mmol) and tetramethylammomum hydroxide (2.38 g, 26.1 mmol) were added to acetonitrile (150 mL). The reaction mixtux became homogeneous after stining at room temperature for about an honr. B0CO2 (8.54 g, 39.2 mmol) was added and the mixture was stirred for 2 days, 2.85 g, 13.1 mmol). Acetonitrile was removed under reduced pressure and H2O and Et20.

The aqueous layer was washed with Et20 and then acidified with solid citric acid to pH ~ 3. The aqueous solution was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na2SO4) 3 and the EtOAc was removed under reduced pressure to give 1-tert-butoxycarbonylaminocyclopropanecaxboxylic acid as a white solid (2.32 g) which was used in the next step without further purification. 60

Step 4 To a solution of 1-tert-butoxycarbonylaminocyclopropanecarboxylic acid (2.32 g, 11.5 mmol) in CH 2 Cl 2 (25 mL) at 0 ° C was added A (0-dmrethylhydroxylamine hydrochloride (1.24 g, 12.7 mmol). triethylamine (2.57 g, 3.54 mL, 25.4 mmol), and HATU (4.82 g, 12.7 mmol) The reaction mixture was stirred at room temperature for 4 h. Et al., <RTI ID = 0.0> Et2O-Carblopoyl-CyclopropyI] carbainic </RTI> acid iert-b \ t which was used in the next step rvithout fnrther purificatiom

Step 5 To a 0.05 M solution of [1- (methoxymethylcarbamoyl) cyclopropyl] carbamic acid tert-butyl ester in Et 2 O (80 mL, 4.0 mmol) at room temperature was added dropwise lithium aliEninumhydide (1.0 M in EtaO). 5 mL, 5.0 mmol). The reaction mixture was stirred for another 20 min and then quenched by 6 mL of a solution of KHSO4 in water. The layers were extracted with Et? 0. 1N HCl, saturated NaHCO3, and brine, dried (NaSO4), and concentrated to yield (1-methylcyclopropyl) carbamic acid e7-butyl ester as a colorless oil (393mg) which was used immediately in the next step vvithout further purification.

Step 6 To a solution of (1-formylcyclopropyl) carbamic acid N-butyl ester (393 mg, 2.12 mmol) in CH 2 Cl 2 (4 mL) was added acetic acid (191 mg, 0.182 mL, 3.18 mmol), and cyclopropyl isocyanide (142 mg, 2.12 mmol). (1-tert-Butoxycarbonylaminocyclopropyl) cyclopropylcarbamoyl methyl ester v / hichv / as used in the next step without further purification.

Step 7 To a solution of the acetic acid (14ertLutoxycarbonylaminocyclopropyl) -cyclopropylcarbamoyl methyl ester in MeOH (5 mL) was added 10% NaOH (1 mL). The solution was EtOAc, washed with brine, dried (NaClCh), and concentrated under reduced pressure to yield [l- (cyclopropylcarbamoylbydroxymethyl)] ) cyclopropyl] - 61 61LV 13669 carbaroic acid tert-butyl ester as a yellow oil which was used in the next step without forther purification.

Step 8 A solution of [1 - (cyclopropylcarbamoyUrydroxymethyl) cyclopropyl] carbamic acid tert-butyl ester in CH 2 Cl 2 (5 mL) and TFA (5 mL) was stirred at room temperature for 2.5 h. The reaction was concentrated and chased with toluene to yield 2- (1-Aminocyclopropyl) -A-cyclopropyl-2-hydroxyacetamide, Proceedings as described in Steps 3-8 above but substituting l-axninocyclopropane-carboxyIic acid with l- aminocyclohexanecarboxylic acid provided 2- (1-aminocyclohexyl) -7A cyclopropyl-2-hydroxyacetamide.

Reference F

Synthesis of 3-amino-N'-cyclopropyl-2-hydroxy-3-methylbutyramide

Step 1 To a solution of (2'hydxoxy-1; 1-diethylethyl) -caxbaniic acid ester (284 mg, 1.5 mmol) in CH 2 Cl 2 (5 mL) was added at 0 ° C. Dess-Martin periodic (763 mg, 1.8 mmol). After 1.5 h, a solution of 0.26M ^ 282 (¼ in saturated NaHCO3 (6 mL) was added and the resulting layer was extracted with CH2Cl2, The combined organic layers were diied (Na2SO4) and concentrated to yield (1,1-dfonethyl-2-oxo-ethyl) carbamic acid tertAmty ester as awhite solid which is used in the next step without fiery purification.

Step 2 To a solution of (1,1-dimethyl-2-oxo-ethyl) -carbamic acid tert-butyl ester in CH 2 Cl 2 was added acetic acid (180 mg, 0.172 mL, 3.0 mmol) and cyclopropyl isocyanide (101 mg, 1.5 romol). Acetylic acid 2-fluoro-butoxycarbonylamino-1-cyclopropylcarbamoyl-2-methylpropyl ester which was used in the next step without further purification. 62

Step 3 To a solution of acetic acid 2-tert-butoxycarbonylamino-1-cyclopropylcafbamoyl-2-methylpropyl ester in MeOH (10 mL) was added 10% NaOH (1.5 mL). 3 h and then acidified 1N Hydrocbloric acid to pH 7. The reaction inixture was extracted with EtOAc. The organic layer (s) (Na 2 SO 4) concentrated to yield (2-cyclopropylcarbarooyl-2-hydroxy-1 J-dimethyl-l) -carbarnic acid / erf-butyl ester which was nsed in the next step v / ithout further purification.

Step 4 A solution of (2-cyclopropylcaxbamoyl-2-hydroxy-1,1-dimethylethyl) -carbamic acid tert-butyl ester in CH2Cl2 (10 mL) and TFA (5 mL) was stirred at room temperature for 4 h The reaction mixture was then concentrated and chased with toluene to yield 3-amino-TV-cyclopropyl-2'hydroxy-3-methylbutyride.

Reference G

Syntbesis of 3-amino-N-benzyl-2-hydroxy-3-methylbutyrainide

? H H

3-Amino-N-benzyl-2-hydroxy-3-methyl-butyl-3-amino-Ar-cyclopropyl-2-hydroxy-3-methyl-butyramide-substitution cyclopropyl isocyam.de with benzyl isocyanide.

Example 1

Synthesis of 2-oxo-3 (.5) - {3- (pyrid-3-ylmethesulfonyl) -2 (R) - [2,23,2-trifluoro-1 (1S) - (4-fluorophenyl) ethylanmio] propionyl} acyl} acid cyclopropylaxoide

63 63LV 13669

Step 1 Catecholborane (19.4 mL, 182 mmol) in dicllorometbane (15 mL) was added to dichloromethane solution of β-methyl CBS oxazaborolidines (13 mL, 13 mmol) and 2,2,2,4'-tetrafluoroacetopheone ( 18.2 mL, 130.13 mmol) dropv / self at -78 ° C in 30 min. The reaction mixtuie was stinred at -78 ° C ovemight. The reaction mixture was quenched with 4N HCl (13 mL) in dioxane at -78 ° C, and the solvent was removed. 10% NaHSCL solution (200 mL) was added to the aqueous layer was exfractedby hexane. The organic layer was washed with water and dried with MgSCL Solvent was removed under the reduced pressure to give.2,2,2-tlufluoro-1 (7?) - (4-fluorophenyl) -ethanol (20 g) as colorless oil ( 90% ee).

Step 2 NaH (11.87 g, 296.7 mmol) was added to Et 2 O (700 mL) at 0 ° C under N 2 followed by addition of an Et 2 O solution of 2,2,2-tzifluoro-1 (f?) - ( 4-Fluorophenyl) ethanol (44.3g, 228.2 mmol). The reaction mixture was transferred for 10 min at 0 ° C then Ih at room temperature. Ethyl fluoromethane sulfonyl chloride (50 g, 296.7 mmol) in Et 2 O / ml added at 0 ° C under reaction mixture was stirred for 10 min at 0 ° C then 3h at room temperature. The solvent was removed under reduced pressure and H 2 O (100 mL) was added slowly. The solvent was dissolved in MgSO4, and the solvent was removed to give trifluoromethanesulfonic acid 2,2,2-trifluoro-1 (K) - (4-fluorophenyl) ethyl ester (70 g) as colorless oil.

Step 3 2 (i) - Amino-3-tritylsulfanylpropionic acid (78 g, 214.6 mmol) dissolved in CH 2 Cl 2 and DIPEA (112 mL, 643.8 mmol) was added to the reaction mixture. 10 min at room temperature. Trifluoromethanesulfonic acid2,2,2-thiofluoro-1 (f) - (4-fluorophenyl) ethyl ester (70 g, 214.6 mmol) in CH 2 Cl 2 as a reaction mixture. Solvent was removed in Et 2 O and v / ash with IN HCl, brine and dried over MgSO *. Solvent was removed give 2 (E) - [2,2,2-trifluoro-1 (E) - (4-fluorophenyl) ethylanxo] -3-tritylsulfanylpropionic acid (90 g) as a yellow solid. 64

Step 4 '2 (f) - [2,2,2-trifluoro-4 (15) - (4-fluorophenyl) ethylamino] -34-sulphanylpropionic acid (5.4 g, 10 mmol) was dissolved in CH 2 Cl 2 and TFA (3 g). 1 mL, 40 mmol) was added at 0 ° C under N2. EtaSiH (3.2 mL, 20 mmol) was added at 0 ° C and the reaction was mixed with room temperature. After stirring for 2 h, the solvent was removed in 1NNaOH (120 roL). The aqueous layer was extracted with hexane. To the aqueous solution of dioxane (120 mL), 3-picolyl chloride hydrochloride (1.97 g, 12 mmol), andtis (2-carboxyethyl) phosphinehydrochloride (280 mg, 1 ramol) we added. The reaction mixture was at the room temperature ovemight. Dioxane v / as removed under the reduced pressure. The solution was adjusted to pH 3 and vvith ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give 3- (pyridin-3'ylmethanesulfanyl) -2 (i) - [2,2,2-trifluoro-1 (iS) - (4) -fluorophenyl) -ethylamino] propionic acid which was used in the next step vvithout furtlier purification.

Step 5: To a solution of 3- (pyrid-3-ylmethanesulfanyl) -2 (1H) - [2,2,2-irifluoro-1 (ij) - (4-fluorophenyl) -ethylamino] propioEdc acid ethanol (10 mL), an aqueous solution of ΟΧΟΝΕ® (4.68 g, rninol in 10 mL H 2 O) was added. After 2 h. solvent under reduced pressure. The aqueous layer was dried and dried with MgSO 4 and filtered The filtrate was concentrated under reduced pressure to give 3- (pyrid-3-} lme &amp; anesulfonyl) -2- (A) [2,2,2-trifluoro-1 (jS) - (4-fluorophenyl) ethylainio.o] propionic acid v / hich v / as used in the next step v / ithout furtlier purification.

Step 6 [0197] Amxtureof3- (pyridm-3-ylmethanesulfonyl) -2- (1?) [2,2,2-thiofluoro-1 (i?) - (4? -Finorophenyl) ethylamino] propionic acid (420 mg, 1 mmol), 3 (15) -amino-2-hydroxyhexanoic acid cyclopropylamide (186 mg, 1 mmol) prepared as described in PCT applicationpublication No. WO-02/18369 as compound xiii, HBTU (455mg, 1.2mmol), and NMM (0.44mL, 4mmol) in acetonitrile w / w at room temperature ovemight. Sat. NH 4 Cl (10 mL) and ethyl acetate (10 mL) were added after 20 min. The combined organic extracts were dried and dried by MgS04, filtered and concentrated by 2-hydxoxy-3 (5) - {3- (pyri (lin-3- 65 65 EN 13669) ybnethanesulfonyl) -2 (P) - [2,2,2-Hiphioro-1 (15) - (4-fluorophenyl) -ethylamino] propionylamino} -hexanoic acid cyclopropylamide which is used in the next step without further purification.

Step 7 To a solution of 2-Hydroxy-3 (6) - {3- (pyrid-3-ylmethylsulfonyl) -2 (R) - [2,252-trifluoro-l (&lt; S) - (4- fhmrophenyl) ethyammo] propionylarnino} hexanoicacidcyclopropylarnide (590 mg, 1 mmol) in 'methylene chloride, DMP was added slowly. The reaction mixture was stirred at room temperature for 30 min and then at 0.26 M Na ^OO in sat. NaHC03 was added. The reaction mixture was mixed for 20 min. 2-Oxo-3 (iS) - {3- (pyridin-3-ylmethmesulfonyl) ~ 2 (ū) - [2] 2,2-Trifluoro-1- (6) - (4-fluorophenyl) ethylamino] propionyl} hexanoic acid cyclopropylamide which was purified by flash column (2% MeOH-CH 2 Cl 2) to give pure product as a yeliow solid. 1 H NMR (DMSO-d 6): δ 0.80 (m, 12H), 2.02 (m, 1H), 3.3-3.7 (b, 3H), 4.00 (m, 1H), 4.46 (m. 1H), 4.79 (m, 2H), 7.25 (m, 2H), 7.50 (m, 2Ή), 7.65 (b, 1H), 7.72 (d, 1H), 8.01 (d, 1H), 8.71 (m, 3H). LC-MS: 587 (M + 1), 585, (M-1), 609 (M + 23).

2-Oxo-3 (6) - {3- (cyclopropylmethanesulfonyl) -2 (.S) - [2,2,2-trifluoro-1 (Proc.) As described above 5) - (4-Fluorophenyl) ethylamino] -propionylamino} hexanoic acid cyclopropylaroide (compound 1). N-NMRpMSO-dg): δ 0.32-0.41 (m, 2H), 0.53-0.67 (m, 6H), 0.8l (t, J = 7.2Hz, 3H), 1.06-1.38 (m, 4H), 1.52- 1.61 (m, 1H), 2.69-2.76 (m, 1H), 2.98 (dd, 1 = 2.8¾ J = 14.SHz, 1H), 3.19 (dd, J = 8Hz, J = 14Hz, 1H), 3.28- 3.50 (m, 3H), 3.82-3.88 (m, 1H), 4.37 (quint, = 7.6µl 1H), 4.70-4.76 (m, 1H), 7.22 (t, 1 = 8.4µ2H), 7.43 (dd , 1 = 5.6¾ 1 = 8.4¾ 2H), 8.51 (d, 1 = 7.2¾ 1H), 8.73 (d, 1 = 5.2¾ 1H), LC-MS: 550 (M + 1), 548, (MH +) . 66

Example 2

Synthesis of 2-oxo-3 (6) -3- [2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridyl-3-ylmethanesulfonyl) propionylamino] pentanoic acid cyclopropylamide

Step 1 {0201} To a -7S ° C methylene chloride solution (75 mL) of 2,2,3,3,3-pentafluoropropan-1-ol (1.5 g, 10.0 mmol) and DEPEA (6.1 mL, 35.0 mmol) added triftic aohydide (1.78 mL, 10.5 mmol). After 2.5 h, S-thesis on the next step at 0 ° C for 80 min. The reaction mixture is at RT for 18 h and then concentrated on the rotovap. Ethyl acetate was added and the reaction mixture was washed vvith 1N HCl. The organic layer is magnesium sulfate, filtered and concentrated. (3 hexanes / ethyl acetate + 1% acetic acid) to provide 2 (E) - (2,2,3,3,3-pentyloropropylamino) -3-tdtylsulfanylpropionic acid (3.29 g) .

Step 2 (R) - (2,2,3,3,3-Pentafluoropropylamino) -3-tritylsulfanylpropionic acid (1.05 g, 2.12 mmol) was added to TFA (0.653). mL, 8.48 mmol) followed by triethylsilane (0.677 mL, 4.24 mmol). The reaction mixture was mixed for 1.5 h at room temperature and then concentrated on the rotovap. The residue was added 2N NaOH solution (20 mL) and the reaction mixture was extracted in hexanes. The NaOH layer was added to thi (2-carboxytriethyl) phosphine hydrochloride (60 mg) follovved by 3-picolylchloiide hydrochloride (348 mg, 2.12 mmol). After 1.5 b, the reaction mrsture was acidified with conc. HCl to ~ pH = 4 and extracted v / ith ethyl acetate. 2 (2) - (2,2,3,3,3-Pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfanyl) propionic acid (530 mg). 67 67LV 13669

Step3 To 2: (5) - (2,2,3,3,3-pentafluoropyropylano) -3- (pyridin-3-ylmethanesulfonyl) pyrophenic acid (151 mg, 0.44 mmol). S) -ammo-2-hydroxypentanoic acid cyclopropylamide hydrochloride (92 mg, 0.44 mmol), EDC (102 mg, 0.66 mmol), and HOBt liydrate (71 mg, 0.53 mmol) was added as N-methylmoiphol (0.194 mL, 1.76 mmol) . The reaction mbcture was stimulated for 2 h and then diluted with ethyl acetate and washed with sodium bicarbonate solution. 2-hydroxy-3 (6) - (2 (5) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfanyl) propionylamino] pentanoic acid cyclopropylamide Concentration of the organic layer 170 mg).

Step 4 To anNMP solution of 2-hydroxy-3 (1S) - [2 (5) - (2,2,3,3; 3-pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfanyl) propionyl] pentanoic acid cyclopropylamide (170 mg, 0.34 mmol) was added an aqueous solution of of® (209 mg, 0.34 mmol). After 2 h, more ΟΧΟΝΕ ® (105 mg, 0.17 mmol) was added with additional waterplus some methanol. After an additional lh 40 min, the reaction mixture was diluted with ethyl acetate and washed with water. 2-hydroxy-3 (5) - [2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridin-3-ylmethylsulfonyl) propionylamino] pentanoic acid cyclopropylamide (176 mg).

Step 5 To a heterogeneous mixture of 2-hydroxy-3 (d) - [2 (5) - (2,2,3,3,3-pentafluoropropylamino) -3- (pyridin-3-ylmethanesulfonyl) propionyl]] pentanoic acid cyclopropylamide (176 mg, 0.33 mmol) in methylene chloride was added Dess-Martin periodinane (183 mg, 0.43 mmol). The reaction mixture became more heterogeneous after a couple of minutes. After 3 h, acetonitrile (3 mL) was added by NMP (6 mL) to give a homogeneous reaction, Additional Dess-Martin periodinane (100 mg). After an additional 70. min of ringing, the reaction mixtux was diluted vrith ethyl acetate and washed rvith sodium bicarbonate solution. The organic layer was separated and concentrated. Flash chromatography (95% methylene chloride / 5% methanol) of the residue provided by a 1: 1 IPA / ethanol mole and allovved to evaporate to provide 2-oxo-3 (i5) -3- [ 2 (R) - (2,2,3,3,3-Pentafluoropropylamino) -3- (pyridyl-3-ylethanesulfonyl) propionylamino] pentanoic acid cyclopropylarnide (87 mg). 68

Ex'2rnple 3

Synthesis ofM- (1-cyclopropylaninoxalylcyclopropyl) -3-cyclopropylmethanesulibnyl-2 (R) - [2,2,2-trifluoro-1 (15) - (4-fluorophenyl) ethylanrino] propion &amp; mide

rS02

Step 1 To azithionophen-3-cyclopropyhnethanesulfanyl-2 (ic) - [2,2,2-1-trifluoro-1- (15) - (4-fluorophenyl) ethylamino] -propionic acid (148 mg, 0.42 mmol), prepared as described in example Γ above, by substitution of picolyl chloride vrith cyclopropylmethyl bromide, and 2- (1-aminocyclopropyl) -Mycyclopropyl-2-hydroxyacetamide (108 mg, 0.63 mmcl) iniV-Me {shampoo Olidme (6 mL) α 0 ° C was added NAr-diethy] propylamine (272 mg, 0.37 mL, 2.11 roinol), and HATU. 4 hours ai rooin temperature. EtOAc and v / ashed with H2O. The organic layer was dried (Na2SO4) and concentrated to yield A- [1- (cyclopropylcarbamoyl-hydroxy-methyl) -cyclopropyl] -3-cyclopropylmethylsulfanyl-2- [2,2,2-trifluoro-1- (4-fluoro-phenyl) -yl] -carbamide ] propionarnide which v / as convertible to the title compound as described in Example 2, steps 4 and 5 above. MS (534.2 M + 1, 532.1 M-1). . Example 3 above but substituting 2- (1-Amino-cyclopropyl) -N-cyclopropyl-2-hydroxyacetaEnide vvith 3-amino-iT-benzyl-2'hydroxy-3-methylbutyxamideprovidedV-benzyl- 3- {3-Cyclopropyl-pyranethanesulfonyl-2 (R) - [2,2,2-trifluoro-1- (15} - (4-fluoro-phenyl) -ethylamino] -propionylamino} -3-methyl-2-oxo-butythane. MS (586.3) M + 1, 584.3 M).

Example 2 above but substituting 2- (1-Amino-cyclopropyl) -N-cyclppropyl-2-hydroxyacetanxide with 3-amino-N-benzyl-2-hydroxy-3-methylbutyramide and 2 (i) ?) - [2,2,2-Trifluoro-1 (1S) - (4-fluorophenyl) ethylamino] -3-tritylsulfanylpropionic acid with 2 (R) - [2,2,2-trifluoro-l (s) - (4-Fluorophenyl) ethylamino] -3-tritylsulfanylpropionic acid provided N-benzyl-3- {3-cyclopropylmethane sulfonyl-2 (7?) - [2,2,2-trifluoro-1 (R) - (4-fluorophenyl) ethylamino ] propionylamino} -3-methyl-2-oxo-butyramide. N-Benzyl-3- {3-cyclopropylmethylenesulfonyl-2- [2,2,2-trifluoro-1- (4-fluoro-phenyl) -ethyl] -amino] -propionylamino} -3-methy-2-oxo-butyramide (586.1 M +1.584.1 Ml). 69 69LV 13669 Follow-up procedure described in Example 2 above but substituting 2- (1-amino-cyclopropyl) -Arcyclopropyl-2-hydroxyacetamide with 3-amino-N-cydopopopyl-2-hydroxyoxy-3-methylbutyrain Cyclopropyl-3- {3-cyclopropylmethanesulfbnyl-2 (E) - [2,2,2-trifluoro-1 (E) - (4-fluoro-phenyl) -ethylamino] -propionylamino} -3-methyl-2-oxo-butyrenes . MS (536.0 M + 1, 534.2 M-1).

Example 4

Syntbesis of 3 (1S) - [3-cyclopropylmethmesdfonyl-2 (E) - (2,2,3,3,3-pentafluoropropylthio) propionylamino] -2-oxo-pentanoic acid cyclopropylamide

Step 1 To -78 ° C Dichiororaethane Solution (75 mL) of 2,2,3,3,3-pentafluoropentan-1-ol (1.5 g, 10.0 mmol) and DIPEA (6.3 mL, 35.0 mmol) ) was added trifilic anhydride (1.78 mL, 10.5 mmol) dropwise. Afier 2h and 20roin, S-triyl cysteine was added to the reaction and filtration continued for Ih and 15 min at room temperature. (3: 1, hexanes / ethy3 acetate with 1% acetic acid) to provide 2 (i?) - (2,2,3,3,3-) pentafluoropropylanimio) -3-trityl-trifluoro-propionic acid (3.29g).

Step 2 Dichloromethane solution of 2 (R) - (2,2,3,3,3-pentafluoropropylamino) -3-thiol sulfanylpropionic acid (1.05 g, 2.12 mmol) was added TFA (0.653 mL, 8.48 mmol) fo] lowed by triethylsilane (0.677 mL, 4.24 mmol). The reaction mixture was stained for 20 min at room temperature and then concentrated on the rotovap. To the residue was added 2N NaOH and hexanes. The mixtnre was shaken and the NaOH layer separated. To the NaOH iayer was added cyclopropylmethyl bromide (0.206 mL, 2.12 mmol). The reaction mixture was mixed with 1N HCl and the product extracted into ethylacetate. 2 (i $) - (2,2,3,3,3-pentafluoropropylamino) -3- (cyclopropyl-methanesnlfanyl) piopionic acid (428 mg) ).

Step 3 To a mbcture of 2 (fi- (2,2,3,3,3-pentafluoropropylamino) -3- (cyclopropy-methanesulfanyl) propioric acid (150 mg, 0.49 mmol), 3 (iS) -arnino -2-hydroxy-pentanoic acid cyclopropylamide hydrochloride (102 mg, 0.49 mmol), EDC (114 mg, 0.74 mmol) and HOBt (79 mg, 0.59 mmol) in dichlornethane was added to 7 Vhnethylmoiphol (0.215 mL, 1.96 mmol). 2-hydroxy-3 (.5) - [2 (iJ) - (2 2,3,3,3-peniafluoro-propylanmo) -3- (cyclopropylmethane-sulfanyl) propionylamino] pentanoic acid cyclopropyIamide (169 mg).

Step 4 To An NMP Solution (5 mL) of 2-Hydroxy-3 (jS) - [2 (E) - (2,2,3,3,3-pentafinoropropyl-ammo) -3- (cyc) opropylamide lanesulfanyl) propionylamino] pentanoic acid cyclopropyl amide (169 mg, 0.37 mmol) was added as a solid (5 mL) of ΟΧΟΝΕ (342 mg, 0.56 mmol). After stirring for 2 h at room temperature (228 mg) was added along with methanol (5 mL). After stirring for additional 2 h. ths reaction was diluted with ethylacetate and Tvashed with a sat'd brine solution. Dichloromethane (10 mL) and Dess-Martin periodic.

This is Leterogeneous rnixture wss added to acetonitrile (3 mL) ibllowed by NMP (6 mL) which. provided a homogeneous reaction. After 5 h, the reaction was diluted with vinyl bicarbonate solution. The organic layer was dried and concentrated. To this vfhite solid was added ethanol and the mbcture was heated to reflux. The style of the heterogeneous mixture was allovred to 115%. M. pt 196.1-196.7 DC.

[0214] Proceeding as above the following compounds were prepared:. Α-cyclopropyl-3β- (3-he] isenesulfonyl-2β- [2,2,2-trifluoro-1X (4-fluoro-phenyl) -ethylamino] -propionylamino} -2-oxo-pentanxide, LC-MS 558 ( M + H); and 77-cyc3-propyl-35 '- [3-cyclopropy] methanesulfonyl-2H- (2,2,3,3,4,4,4-heptafluoro-butylamino) -propionylamino] -2-oxo-pentaxLaDide, LC- MS 542 (M + H). 71 71LV 13669 Eleample 5

Syntheis of ΤΤογοΙορΓοργΙ-Β # - {4-Methanesulfonyl-2'S '- [2; 2J2-trifluoro-1S' - (4-fluoro-phenyl) -ethylamino] -butyrylamino} -2-oxo-pentanamide

{0215] (6) Methyl 2-anWo-4-methyIsulfanylbuiyrate hydrochloride (750 mg, 3.76 mmol) and 2,2,2-trifluoro-1- (4-fluorophenyl) ethanone (721 mg, 3.76mmoI) was dissolved inmethanol (15 mL) and potassium carbonate (1.04 g, 7.52 mmol) were added to the solution. The mizture wss stretched at 55 ° C for 23 hours and was concentrated on dryness on a rotovap. The residue was combined with toluene (20 mL) and the rnixture was concentrated to dxyness on a rotovap. The residue was combined with acetonitrile (10 mL) and the mixture was stirred at about -30 ° C. Zinc borohydride, prepared by adding a 1 M zinc chloiide solution in ether (5.64 mL) to stir the borohydride (427 mg, 11.28 mmol), stirriugin ether (lOmL) and stirring for 19 hours. approximateiy 7 honrs at reduced temperature and skin 16 hrs ai room temperature. The reaction misture was quenched with 1N HC3, and was washed with brine (2X50mL). 2- [2- (2-Fluoro-1-fluorophenyl) -5- (4-fluorophenyl) ethylannno] -4-methylsulf3nylbutyiic acid (1.15 g) as solid.

2'S- [2,2,2-Tri: Thio-11,5- (4-fluorophenyl) ethylamino] -4-methylphenyl] ynylbutyric acid (150 mg, 0.46 mmol), cyclopropyl 36-anhno-2-hydroxypentanamide hydrochloride ( 106 mg, 0.51 mmol), EDC (132 mg, 0.69 mmol) and HOBt (75 mg, 0.55 mmol) were combined in DCM (10 mL) and the 7V-methylmorpholme (0.253 mL, 2.3 mmol) was added. was added. The mixture was mixed for 2 hours and then diiuted with ethy] acetate. The mixture was washed with sodium bicarbonate solution (2X35mL) and the organic layer was dried and concentrated to provide N-cyclopropyl-2-hydroxy-3S- {4-methanesulfonyl-2'-5,2,2,2-trifluoro- 16 '- (4-Fluoro-phenyl) -hexylamino] -butyrylamino} -pentanamide (188 mg) as a white solid.

N-Cyclopropyl-2-hydroxy-3β- {4-methanesulfonyl-2- [23232-trifluoro-1; 5- (4-fluoro-phenvl) -ethylamino] -butyryl-quino} pentanarnide (188 mg, 0.39 mmol) was dissolved in 1- 72 methyl-2-pyrrolidinone (5 mL) and the solution was added to the temperature solution of the oxone (5 mL, 434 mg, 0.71 mmol) was added. The mixture was stretched for lhour and 45 minutes and then diluted vrith ethyl acetate. The mbcture was washed with brine (3X25mL) and the organic layer was dried and concentrated. The residue was dissolved in 1-methyl-2-pyrimolidinone (5 mL) and then Less-Martin (232 mg, 0.55 mmol) was added to the solution. The reaction v / s allowed for 1 hour and then the solution was diluted v / ith ethyl acetate. The mixture was washed with sodium bicarbonate solution (3X30mL) and ths organic layer was dried and concentrated. N-cyclopropyl-3'S'- {4-methanesulfonyl-2 '- (2,2,2-trifluoro-liS, - (4)) -fluoro-phenyl) -ethylanino] -butyrylino} -2-oxo-pentanamide (114mg) as awhiiesoide (mp 152.5r153.5 ° C) LC-MS 510 (M + H).

Biohealthy Examples Esample 1

Cathepsin B Asssv Solutions of cormorants in varying concentraticns for 10 pL of dimethyl sulfate (DMSO) and .then diluted into assay buffer (40 pL, including: N / 7-bis (2-hydroxyetiay!) - 2 -ammoethanesuhonic acid (BBS), 50 mM (pH 6), monolaurate of ololyoxyeeaeaorbitan, 0.05 ° / o, and dithiothreitol (DTT), 2.5 µm). Human cathepsin B (0.025 pMoles in 25 pL of assay buffer) was added to the dilutions. The assay solutions are mixed for 5-10 seconds at a 30 min at room temperature. Z-FR-AMC (20 nMoles in 25 pL of assay buffer) was added to the assav. Solutions and hydrolysis was fcllcv / ed spectrophotometrics (λ 460 nm) for 5 min. Apparent inhibition constants (K, ·) were calculated from the enzyme progress curves using Standard mathematical models.

Compounds of the invention were the above-described assay and observed to exhibit cathepsin B inhibitory activity. 73 73LV 13669

EXAMPLE 2 Cathepsin KAssay Solutions of the compound in varying concentrations -vere prepared in 10 pL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5) mM; and DTT, 2.5 mM). Human cathepsin K (0.0906 pMoles in 25 pL of assay buffer) was added to the dilutions. The assay solutions were mixed for 5-10 seconds at a 30 min at room temperature. Z-Phe-Arg-AMC (4 µMoles in 25 pL of assay buffer) was added to the assay at (λ 460 mn) for 5 min. Apparent inhibition constants (3¾) were calculated by the standard mathematical models.

Compounds of the invention v / ere body by the above-described assay and inhibited cathepsin K inhibitory activity.

Example 3 '

Cathepsin L Assay [0222] Solutions of the Inverting Compounds of the Dosage of Dimethy] sulfoside (DMSO) and then diluted into assay buffer (40 pL, including: MES, 50 mM (pH 5.5): EDTA, 2.5 mM) .and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles in 25 pL of assay buffer) was added to the dilutions. The assay solutions weremixed for 5-10 seconds on a shaker plate, covered and incubated for 30 min at room teioperature. Z-Phe-Arg-AMC (1 nMoles in 25 pL of assay buifer) was added to the assay solution (λ 460 rau) for 5 min. Apparent inhibition constants (K, ·) were calculated from the enzyme progress curves using Standard mathematical models.

Compounds of the invention were described by the above-described assay and inhibited cathepsin L inhibitory activity.

Eiample 4 Cathepsin S Assay Solutions of the compounds of varying concentrations were prepared in 10 µL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 µL, containing: MES, 50 mM (pH 6.5); EDTA, 2.5) mM; and NaCl, 100 mM); β-mercaptoethanol, 2.5 mM; andBSA, 0.00%. Human cathepsin S (0.05 pMoles in 25 pL of assay buffer) was added to the dilutions. 74

The Assay Solutions were icdxed for 5-10 seconds at a 30 min ai room temperature. Z-Val-Val-Arg-AMC (4 nMoles in 25 pL of assay buffer containiag 10% DMSO) was spectophotomstrically (ai λ 460 nm) for 5 min. Apparent inhibition constants (Kj) were calculated from the enzyme progress cuives using Standard raathematical models.

[0225J Compounds of the Invention by the above-described Assay and Inhibitory Activity of &lt; or = 100 nm.

Example 5 Caihepsin F Ass ay Solutions of the compound compounds of the study of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 pL, comprising: MES, 50 mM (pH 6.5); 2.5 mM and NaCl 100 mM); DTT, 2.5 mM; andBSA, 0.01%. Human cathepsin F (0.1 pMoles in 25 uL of assay bufier) was added to the dilutions. The assay solutions were mixed for 5-10 seconds at a 30 min at room temperature. Z-Phe-Arg-AMC (2 nMoles in 25 pL of assay buffer containing 10% DMSO) was followed by spectrophoiometrically (at λ 460 nm) for 5 min. Apparent inbibition constants (Kj) were calculated from the enzyme progress curves using Standard maihematical models.

Compounds of the invention were the above-described assay and inhibitory factor inhibition.

Evample 1

Representativepharmaceuiical foimulations Containing a Compound of Formula (I)

ORAIFORMULATION

10-100 mg 105 mg 18 mg q.s. to 100 mL

Compound of Formula (I) Citric Acid Monohydrate Sodium Hydroxide Flavoring Water 75 75LV 13669

INTRAVENOUS FORMULATION

Compound of Formula (3) 0.1-10 mg Dextrose Monohydrate o.s. it is isotonic Citdc Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18 mg Waier for Injection q.s. to 1.0 mL TABLETFOKMLATION Compormd of Formula (I) 1% Microcrystalline Cellulose 73% Stearic Acid 25% Colloidal Silica 1% [0228] For the foregoing invention has been described in some of the cases. You can find one of the slideshows that you can use in your application. Therefore, it is to be a description of the above mentioned description. The scope of the invention should, therefore. as a matter of course, but a shosld is a detoxified wiih reference to the follovdng appended claims; 1 1 EN 13669

CLAIM 1. A compound ofFuloula (I):

. R1 is hydrogen or alkyl; R2 is cycloalkyl, cycloalkylalkyl, aralkyl, heteroaryl, or heteroaralkyl optionally substituted by one or two substituents mdependently selected from alkyl, alkoxy, or halo; C is alkyl or alkoxyalkyl; . R4 is hydrogen or alkyl; or RJ and R4 together with the carbon atom to which they are attached, cycloalkylene or substituted with one to four halo or heterocycloalkylene optionally substituted with alkyl, alkoxyalkyl, hydroxyalkyl, acyl, cycloalkyl, cycloalkylalkyl, or haloalkyl; . R5 is alkyl, haloalkyl substituted substituted with cycloalkyl. allyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocycloalkynyl, - (allyl) -X-R9 (where X is -O-, -S-, -SO-, -SO2-, -CONH-, -NHCO-, or -NHSO 2 - and R 9 is alkyl: haloalkyl, cycloalkylalkyl, allyl, aralkyl, heteroaryl, heteroaxalkyl, heterocycloalkyl; or heterocycloalkylalkyl, or- (alkylene) -X 1 - (haloalkylene) -R 10 (wherein X 1 is -O-, - S-, -SO-, -SO2-, -CONH-, -NHCO-, or -NHSO2- and R10 is cycloalkyl, allyl, heteroaryl, or heterocycloalkyl, wherein the aromatic or alicyclic ring in R5 is optionally substituted with one, two, or three Ra selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halo; selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one Rc selected from cyano, hydroxyalkyl, alkoxyalkyl, amirioalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, acylalkyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl,. heteroaryloxycarbonyl, heteroxyalkyloxycarbonyl, heterocycloalkyloxycarbonyl, 2 cycloalkylxycafonyl3 aryloxy3 heteroaryloxy3 arylloxy, heteroaralkyloxy, aminocarbonyl3 aminosulfonyl, or -SO2Rn (where R11 is alkyl3 axyl3 heteroaryl 13 or heterocycloalkyl); and. furthermore, selected from alkyl, haloalkyl 3 alkoxy, hydroxy, haloalkoxy, orchalo; .

Rd is haloalkyl; R7 is hydrogen or baloalkyl; and

Rs also hydrogen, alkyl, haloalkyl, cycloalkyl3 aryl, heteroaxyls heterocycloalkyl attached to the carbon atom aromatic or alicyclic ring in Rs is also substituted with one3 two or three Re and selected from alkyl3 halo, haloalkyl, hydroxy3 alkoxy3 haloalkoxy3 alkoxycaxbonyl3 carboxy3 cyano3 alkylsulfonyl , or aminosulfonyl; or aery-acceptable salts. 2. The compound of Claim 1 wherein R1 is hydrogen and R2 is cyclopropyl, 1-phenylethyl, or liT-pyrazol-5-yl. 3. The compound of Claim 1 is hydrogen and R 1 is cyclopropyl. 4. The compound of Claim 2 or 3 is hydrogen and R4 is alkyl. 5. The compound of Claim 2 or 3 is hydrogen and R4 is methyl, ethyl, propyl or butyl. - 6. The compound of Claim 2 or 3 RJ is hydrogen and R4 ethyl. 7. The compound of Claim 2 or 3 is R3 and R4 are alkyl. 8. The compound of Claim 2 or 3 is methyl or ethyl. 9. The compound of Claim 2 or 3 is R3 and R4 are methyl. 10. The compound of Claim 2 or 3 is R3 and R4 together with the carbon atom which they are attached form cycloalkylene. 3 3 EN 13669 11. The compound of Claim.2 or 3, R3 and R4 together with the carbon atoms which they are attached to the main cyclopropylene. 12. The compound of any of the Claims 2-11 R is haloalkyl and R and R are hydrogen. 13. The compound of any of the Claims 2-11, R6 is 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl and R7 and R8 are hydrogen. 14. The compound of any of the Claims 2-11, wherein R6 is haloalkyl, R7 is haloalkyl, s andR ishydrogen. A 7 15. The compound of any of the Claims 2-11 wherein R is haloalkyl, R is alkyl, and R 8 is hydrogen. 16. The compound of any of the Claims 2-11 R is haloalkyl, R is hydrogen, and R8 is aryl optionally substituted with one, two, or tliree Re. 17. The compound of any of the Claims 2-11, R6 is trifluoromethyl or difluoromethyl, R7 is hydrogen, and R8 is 4-fluorophenyl; 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluoro-phenyl. . ~. 18. The compound of any of the Claims 2-11 R is haloalkyl, R is hydrogen, and R8 and R8 are heteroaryl optionally substituted with one, 'two, or tbree Re. .19. The compound of any of the Claims 2-18 and R5 is cycloalkylalkyl optionally substituted with one, two, or one or more of selected from aralkyl or heteroaralkyl. 20. The compound of any of the Claims 2-18, R5 is 1-methylcyclopentylmethyl, 1-methylcyclohexyl, lrmethylcyclobutyl, 1-methyl-3,3-difluorocyclobutylmethyl, 1-methyl-4,4-difluorocyclohexylmethyl, Tberrzyl-cyclopropylmethyl, Tthiazol -2-ylmethylcyclopropyl-methyl, or i-methyl-3,3-difluorocyclopentylmethyl.

21. The compound of any of Clals 2-18, R5 is alkyl. 22. The compound of 311) is a haloalkyl substituted v / ith aryl, heteroaryl or heterocycloalkyl. 23. The compound of any of the Claims 2-18 is R5 is 2,2-difluoro-3-phenylpropyl, 2,2-difluoro-3-tetrahydropyran-4-ylpropyl, 2,2-difluoro-3-morpholine. -ylpropyl, 2,2-difluoro-3-pyrid-2-ylpropyl, 2,2-difluoro-3-pyridoy-3-ylpropyl, or2,2-dichloro-3-phenylpropyl. 24. The compound of any of the Claims 2-18 wherein R3 is - (alkylene) -S (O)? -R9 whereR9isalkyl. 25. The compound of any of the Claims 2-18, R5 is methylsulfonylmethyl, ethylsulfonylethyl, propyl-1-sulfonylmethyl, 2-methylpropylsulfonylmethyl, 2-methysulfonylethyl, or 2-ethylsulfonylethyl. 26. The compound of any of the Claims 2-18, R3 is - (allcylene) -S (O) 2-R9 where R9 is also an arylalkyl optionally substituted with one, two, or three independently selected from alkyl, haloIkyl ..alkoxy. hydroxy, haloalkoxy, cyano, or halo; selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl. aryl, heteroaryl, aralkyl, heteroaralkyl 3 cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycafonyl, heteroarylcycloalkyl, aryloxy, heteroaryloxy, aralkylxy, heteroaralkyl, aminocarbonyl, aminosulfonyl, or -SO2R11 (where R11 is alkyl, aryl, heteroaryl, or heterocycloalkyl); selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo. 27. The compound of any of the Claims 2-18, R5 is 2-difluoromethoxyphenyl-methanesulfonylmethyl, 2-phenylsulfonylethyl, 4-fluorophenylmethanesulfonylmethyl, 4-ammonocarbonylphenylmethanesulfonylmethyl, 4-piperazin-1-ylphenylmethylene sulfonylmethyl, 2-fluorophenylmethanesulfonylmethyl, 3-fluorophenylmethanesulfonylmethyl, 4,6-Trifluorophenyhnethanesulfonylmethyl, 2-, 3-, or 5 5 LV 13669 4-trifluoromethylphenylmethanesulfonylmethyl3 phenyhnethanesulfonylmethyl3 2- (2-, 3-, or 4-trifluoromethylphenyl) sulfonylethy], phenyhnethanesulfonyhnethyl3 or 2- (2- , 3-, or 4-fluorophenyl) sulfonylihyl. 28. The compound of any of the Glaims 2-18, R5 is - (alkylene) -S (O) r R9 where R9 is heteroaryl or heteroaralkyl optionally substituted with one, two or three Ra and selected from alkyl3halalkyl3 alkoxy3hydroxy3 haloalkoxy3 cyano3 orhalo; or optionally substituted with one ortwo Rb independently selected from HydroGen3 alkyl3 haloalkyl3 alkoxy3 hydroxy3 haloaIkoxy3 halo, carboxy3 or alkoxycarbonyl and one R c selected from hydroxyaIkyl3 alkoxyalkyl3 aminoalkyl, aryl3 heteroaiyl3 aralkyl, heteroaralkyl, cycloaIkyl3 cycloalkyIaikyl3 heterocycloalkyl3 heterocycIoalkylalkyl3 acyl3 alkoxycarbonyl3 aiyloxycarbonyl3 aralkyloxycarbonyl3 beteroaxyloxycaibonyl3 heteroaralkyloxycarbonyl3 aryloxy. heteroaryloxy3 aralkylxy3 heteroaralkylxy, aminocarbonyl, aminosulfonyl3 or -SO2R11 (whereRn is alkyl3 allyl3 heteroaryl, or heterocycloalkyl); and furthermore, the aromatic or alicyclic ring in Rc is optionally substituted with one of two or three haloalkyl3-alkoxy3 hydroxy3 haloalkoxy, orhalo. 29. The compound of any of the Claims 2-18 R 3 is pyridin-2-ylmethanesulfonylmethyl-pyridin-3-ylmethanesulfonylmethyl, pyridyl-4-ylmethanesulfonylmethyl, 3-difluoro-methoxy-pyridin-2-ylmethanesulfonylmethyl, 2-difluoromethoxy-pyridin-3-imidazane sulfonylmethyl3-4-difluoromethoxypyridin-3-ylmethanesulfonylethyl, 3-difluoromethoxy-pyridin-4-ylmethanesulfonylmethyl-3-pyrimidin-2-ylmethanesulfonylmethyl-pyrimidin-5-ylmethanesulfonylmethyl-3-trifluoromethyl-pyridin-2-ylmethanesulfonylmethyl-4-trifluoromethyl-pyridin-3-ylmethanesulfonyl-pyridin-3-ylmethanesulfonylmethyl] 2-fluorophenan-5-ylmethanesulfonylmethyl, 2-methylthiazol-4-ylmethanesulfonyl-tetrahydro-2-ylmethanesulfonylmethyl-2-pyrimidin-2-ylmethanesulfonylmethyl, 2-pyridin-3-ylethanesulfonylmethyl, 2-pyridin-3-ylethanesulfonylmethyl; -ylethanesulfonylmethyl, 2-pyridin-3-ylsulfonylethyl, 2-pyridin-4-ylsulfonylethyl-3-pyridin-3-ylsulfonylpropyl, 1,335-triazin-2-yl-methanesulfonylmethyl-1,3,4-thiadiazol-2-ylmethane ulfonylmethyl-3-oxazol-5-ylmethanesulfonylmethyl, thiazol-5-ylmethane-sulfonylmethyl-3-thiazol-2-ylmethanesulfonylmethyl. . 30. The compound of any of the Claims 2-18 and R5 is also (alkylene) -S (O) 2- R9 where R9 is cycloalkylalkyl. 6 31. The compound of any of the Claims 2-18 to R5 is cyclopropyImethanesulfonylmethyl. 32. A phytaceutical composition of the Claims 1-31 in admixture with one or more suitable excipients. Use of a phytaceutical composition of the Claims 1-31 in admixture with one or more excipients for treating a disease in an animal. 34. Use of a compound of claim 31 for treating a disease, rheumatoid arthritis, rhinitis, myasthema ditch, psoriasis, pemphigus vulgaris,. Gravės' disease, myasthenia grāvis, systemic lupus exytliemus, asthma, pain, and atherosclerosis 35. Use of a compound of any type in the patient. . 36. The compound of Claim 1: RJ is alkyl and R4 is alkyl. 37. The compound of Claim 1 vvherein: RJ and R4 together with the carbon atom which they are attached to the background cycloallcylene. . 3, 8-The compound of Claim 1: R3 and R4 together with the carbon atom to which they are attached piperidin-4-yl at the nitrogen atom with ethyl, 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran- 4-yl, tetrahydrothiopyran-4-yl, or 1,1-dioxotetrahydrothiopyran-4-yl. 39. The compound of Claim 1: R6 is haloalkyl and R7 and R8 are hydrogen. R 40 is haloalkyl, R 7 is haloalkyl, and R 5 are hydrogen. . The compound of Claim 1: R6 is haloalkyl, R7 is alkyl, and R8 are hydrogen. 42. The compound of Claim 1: R 1 is hydrogen, R 2 is cyclopropyl 3 R 3 is hydrogen, R 4 is ethyl 3 R 5 is 2-methylsulfonylethyl3 R 6 is trifluoromethyl, R 7 is hydrogen and R 5 is 4-fluorophenyl, i.e. cyclopropyl-3- { 4-Methanesulfonyl-2- [23232-trifluoro-1- (4-fluoro-phenyl) -ethylamino] -butynylamino} -2-oxo-pentanamide. 43. The compound of Claim 42 which is N-cyclopropyl-3) y- {4-methanesulfonyl-2T- [2,2,2-trifluoro-1R- (4-fluoro-phenyl) -ethylamino] -butyrylamine} -2-oxo-pentanamide. 44. The compound of Claim 1: R1 is hydrogen3 R2 is cyclopropyl3 RJ is hydrogen. R 4 is ethyl, R 5 is 2- {phenylsulfonylmethyl} R is trifluoromethyl; R is hydrogen and R is 4-fluorophenyL-N'-cyclopropyl-3- {3-benzenesulfonyl-2- [2R-2-trifluoro-1- (4-fluorophenyl) -ethylamino] -propionylamino} -2-oxo-pentanamide . 45. The compound of Claim 44 which is N-Cyclopropyl-3S- {3-benzenesulfonyl-2R3- [2,232-trifluoro-1T- (4-fluoro-phenyl) -ethylamino] -propionylamino} -2-oxo-pentanamide. 46. The compound of Claim 1: R1 is also hydrogen3 R2 is cyclopropyl3 R3 is hydrogen3 R4 is also ephyl, R3 is cyclopropylmethylsulfylmethyl3 R6 is also chloropropyl, R7 is hydrogen and R5 is also hydrogen3 n-cyclopropyl-3- [3-cyclopropyhnethanesulfonyT2- 2,2,3,3,434:) 4-heptafluoro-butylamino) -propionylamino] -2-oxo-pentanamide. 47. The compound of Claim 46 is 2-cyclopropyl735r- [3-cyclopropylmethanesulfonyl-2R- (2:, 2,3,334,434'heptafluoro-butylamino) -propionylamino] -2-oxo-pentanamide. . ·

AjBSTRACT

The present invention is based on these proteases, in particular, cathepsins B, K, L, F, and is therefore useful in treating diseases mediated by these proteases. These compounds and processes for preparing them.

Claims (47)

Claims 1. A compound of formula (I): e6 wherein: R 1 is hydrogen or alkyl; R 1 is cycloalkyl, cycloalkylalkyl, aralkyl, heteroaryl or heteroaralkyl optionally substituted with one or two substituents independently selected from alkyl, alkoxy or halogen-containing; R3 is alkyl or alkoxyalkyl; R 'is hydrogen or alkyl; or and R4 together with the carbon atom to which they are attached form cycloalkylene optionally substituted with one to four halogen-containing groups or heterocycloalkylene optionally substituted with alkyl, alkoxyalkyl, hydroxyalkyl, acyl, cycloalkyl, cycloalkylalkyl or cycloalkyl; haloalkyl; R5 is alkyl, haloalkyl optionally substituted with cycloalkyl, aryl, heteroaryl, heterocycloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, heterocycloalkylalkyl, - (alkyl) -X-R9 (wherein X is -O-, -S-, -SO-, -SO 2 -, -CONH-, -NHCO- or -NHSO 2 - and R 9 is alkyl, haloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, hexoalkyl, heterocycloalkyl or heterocycloalkylalkyl) or - (alkylene - th- thalogenalkylene-R 10 (wherein X 1 is -O-, -S-, -SO-, -SO 2 -, -CONH-, -NHCO- or -NHSO 2 - and R 10 is cycloalkyl, aryl, heteroaryl or heterocycloalkyl) wherein R 3 is an aromatic or alicyclic ring optionally substituted with one , two or three Ra independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halogen, or optionally substituted with one or two of R regardless selected from hydrogen, alkyl, haloalkyl, hydroxy, haloalkoxy, halogen-containing group, carboxy or alkoxycarbonyl and one R c selected from cyano, • hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cikloalkilalkilgiūpas , heterocycloalkyl, heterocyclo alkilalkilgrupas, acyl, arylalkyl, alkoxycarbonyl, ariloksikarbonilgiupas, aralkiloksikarbomlgrupas, heteroariloksikarbonilgiupas, heteroaralkiloksikarbonilgrupas, heterocikloalkiloksikarbonilgrupas, cikloalkiloksikarbomlgrupas, aryloxy, heteroaryloxy, aralkyl-oxy, heteroaralkiloksigrupas, aminocarbonyl, aminosulfonyl or a group -SO2R11 (wherein R11 is alkilgmpa, aryl , heteroaryl or heterocycloalkyl); and further, wherein the Rc aromatic or alicyclic ring is optionally substituted with one, two, or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halogen-containing groups; 2 R 6 is haloalkyl; R7 is hydrogen or haloalkyl; and R8 is hydrogen, allyl, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl attached through a carbon atom, wherein the R5 aromatic or alicyclic ring is optionally substituted with one, two or three Re independently selected from alkyl, halogen containing groups, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkoxycarbonyl, carboxy, cyano, alkylsulfonyl or aminosulfonyl; or a pharmaceutically acceptable salt thereof. 1 9 The compound of claim 1, wherein R is hydrogen and R &quot; is cyclopropyl, 1-phenylethyl or li-pyrazol-5-yl. '3. The compound of claim 1, wherein R is hydrogen and R is cyclopropyl. A compound according to claim 2 or 3, wherein R 3 is hydrogen and R 4 is alkyl. A compound according to claim 2 or 3, wherein RJ is hydrogen and R4 is methyl, ethyl, propyl or butyl. A compound according to claim 2 or 3, wherein R 3 is hydrogen and R 4 is ethyl. A compound according to claim 2 or 3, wherein R 3 and R 4 are alkyl. The compound of claim 2 or 3, wherein R 3 and R 4 are independently methyl or ethyl. A compound according to claim 2 or 3, wherein R 3 and R 4 are methyl. A compound according to claim 2 or 3, wherein RJ and R4 together with the carbon atom to which they are attached form a cycloalkylene group. A compound according to claim 2 or 3, wherein R3 and R4 together with the carbon atom to which they are attached form cyclopropylene. A compound according to any one of claims 2 to 11 wherein R 6 is haloalkyl and R 7 and R 8 are hydrogen. A compound according to any one of claims 2 to 11-, wherein R 6 is 2,2,2-trifluoroethyl or 1,1,2,2,2-pentafluoroethyl and R 7 and R 8 are hydrogen. C n A compound according to any one of claims 2 to 11, wherein R is haloalkyl, R is haloalkyl, and R 8 is hydrogen. A compound according to any one of claims 2 to 11, wherein R is haloalkyl, R is alkyl, and R 8 is hydrogen. A compound according to any one of claims 2 to 11, wherein R is haloalkyl, R is hydrogen, and R 8 is aryl optionally substituted with one, two, or a Re. 3 3 EN 13669 A compound according to any one of claims 2 to 11, wherein R 6 is trifluoromethyl or difluoroethyl, R 7 is hydrogen and R 5 is 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6 -, 3,4, or 3,5-difluorophenyl. A compound according to any one of claims 2 to 11, wherein R is haloalkyl, R is hydrogen and R8 and R8 are heteroaryl optionally substituted with one, two or three Re. A compound according to any one of claims 2 to 18, wherein R 5 is cycloalkylalkyl optionally substituted with one, two or three Ra independently selected from alkyl or halogen-containing or R c selected from aralkyl or heteroaralkyl. A compound according to any one of claims 2 to 18, wherein R 5 is 1-methylcyclopentylmethyl, 1-methylcyclohexylgrapa, 1-methylcyclobutyl, 1-methyl-3,3-difluoro-cyclobutylmethyl-methyl, 1-methyl-4,4-difluoro-cyclohexylmethyl, 1 benzyl-cyclopropylmethyl-yl, 1-thiazol-2-ylmethylcyclopropylmethyl or 1-methyl-3,3-difluoro-cyclopentylmethyl. A compound according to any one of claims 2 to 18, wherein R 5 is alkyl. A compound according to any one of claims 2 to 18, wherein R 5 is haloalkyl substituted with aryl, heteroaryl or heterocycloalkyl. A compound according to any one of claims 2 to 18, wherein R 5 is 2,2-aifluoro-3-phenylpropyl, 2,2-difluoro-3-ethrahydropyran-4-ylpropyl, 2,2-difluoro-3-morpholine -1-ylpropyl, 2,2-difluoro-3-pyridin-2-ylpropyl, 2,2-difluoro-3-pyridin-3-ylpropyl or 2,2-dichloro-3-phenylpropyl. A compound according to any one of claims 2 to 18, wherein R 5 is - (alkylene) -S (O) 2 -R 9, wherein R 9 is alkyl. A compound according to any one of claims 2 to 18, wherein R 5 is methylsulfonylmethyl, ethylsulfonylmethyl, propyl-1-sulfonylmethyl, 2-methylpropylsulfonylmethyl, 2-methylsulfonyl ethyl or 2-ethylsulfonyl ethyl. A compound according to any one of claims 2 to 18, wherein R 5 is - (a Hdyl) -S (O) 2 -R 9, wherein R 9 is aryl or aralkyl optionally substituted with one, two or three R a independently selected from alkyl, haloalkyl, alkoxy, hydroxyl, haloalkoxy, cyano or halo; or optionally substituted with one or two Rb independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxy or alkoxycarbonyl, and one Rc selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, arylgroup, heteroaryl , aralkyl, heteroaralkyl, cycloalkyl group, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acilgmpas, alkoxycarbonyl, aiiloksikarbonilgrupas, aralkiloksikarbonil-giupas, heteroariloksikarbonilgrūpas, heteroaralkiloksikarbonilgrupas, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkiloksigrupas, aminokarbonilgiupas aminosulfonyl or -SChR11 (where Rn is alkyl , aryl, heteroaryl or heterocycloalkyl); and further, wherein the Rc aromatic or alicyclic ring is optionally substituted with one, two, or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halogen. 4 A compound according to any one of claims 2 to 18, wherein R 5 is 2-difluoromethoxyphenylmethanesulfonylmethyl, 2-phenylsulfonylethyl, 4-fluorophenylmethanesulfonylmethyl, 4-aminocarbonylphenylmethanesulfonylmethyl, 4-piperazin-1-ylphenylmethanesulfonylmethyl, 2-fluorophenylmethanesulfonylmethyl, 3 -fluorophenylmethanesulfonyl-ethyl, 2,4,6-trifluorophenylmethanesulfonylmethyl, 2-, 3- or 4-trifluoroethylphenylmethanesulfonylmethyl, phenylmethanesulfonyl ethyl, 2- (2-, 3- or 4-trifluoromethylphenylsulfonylethyl, phenylmethanesulfonylmethyl or 2- (2-, 3- or 4-fluorophenylsulfonyl ethyl. A compound according to any one of claims 2 to 18, wherein R5 is - (alkylene) -S (O) 2-R9, wherein R9 is heteroaryl or heteroaralkyl optionally substituted with one, two or three Ra, independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halogen, or optionally substituted with one or two R10 independently selected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, halogen containing group, carboxy or alkoxycarbonyl and one R c selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroarilgmpas, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocyclo alkilalkilgrupas, acyl, alkoxycarbonyl, aryloxycarbonyl, aralkiloksikarbonilgrupas, heteroariloksikarbonilgrupas, heteroaralkyloxy-carbonyl, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl or -SO2Rn (wherein R11 is alkyl, aryl, heteroaryl or heterocycloalkyl); and further, wherein the Rc aromatic or alicyclic ring is optionally substituted with one, two, or three Rd independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halogen. A compound according to any one of claims 2 to 18, wherein R 3 is pyridyl-2-ylmethanesulfonylmethyl, pyridin-3-ylmethylsulfonylmethyl, pyridin-4-ylmethanesulfonylmethyl, 3-difluoromethoxypyridin-2-ylmethanesulfonylmethyl, diylmethoxypyridin-3-ylmethanesulfonylmethyl. 4-Difluoromethoxypyridin-3-ylmethanesulfonylmethyl, 3-difluoro-methoxy-pyridyl-4-ylmethanesulfonylmethyl-pyrimidin-1-ylmethyl-pyrimidin-5-ylmethanesulfonylmethyl, 3-trifluoromethyl-pyridyl-2-ylmethanesulfonylmethyl, 4-trifluoromethyl-pyridin-3-ylsulfonylmethyl, 4-trifluoromethyl-pyridin-3-ylsulfonylmethyl, 3,5 - dimethylisoxazol-4-ylmethanesulfonylmethyl, 2-fluoro-furan-5-ylmethanesulfonylmethyl, 2-methylthiazol-4-ylmethanesulfonylmethyl, furan-2-ylmethanesulfonylmethyl, 2-pyridin-2-ylethanesulfonylmethyl, 2-pyrid-3-ylethanesulfonylmethyl, 2 pyridin-4-yl-ethanesulfonylmethyl, 2-pyridyl-3-ylsulfonyl-ethyl, 2-pixid-4-ylsulfonyl-ethyl, 3-pyridin-3-ylsulfonyl-propyl, 1,3,5-triazine-2-ylmethanesulfonylmethyl, 1, 3,4 thiadiazol-2-ylmethanesulfonylmethyl, oxazol-5-ylmethanesulfonylmethyl, thiazol-5-ylmethanesulfonylmethyl or thiazol-2-ylmethanesulfonylmethyl. A compound according to any one of claims 2 to 18, wherein R 5 is - (alkylene) -S (O) 2 R 9, wherein R 9 is cycloalkylalkyl. A compound according to any one of claims 2 to 18, wherein R 5 is cyclopropylmethanesulfonylmethyl. A pharmaceutical composition comprising a compound according to any one of claims 1 to 31, in admixture with one or more acceptable excipients. 5 5 EN 13669 Pharmaceutical compositions comprising a compound according to any one of claims 1-31. the use of one or more acceptable adjuvants for the treatment of a disease in an animal involved in cathepsin S administration to an animal. Use of a compound according to claim 31 for the treatment of a disease wherein the disease is rheumatoid arthritis, scattered sclerosis, myasthenia ditch, rhinitis, pemphigus vulgaris, Greiva disease, myasthenia ditch, systemic lupus erythematosus, asthma, pain and atherosclerosis. The compound according to any one of claims 1 to 31, according to any of claims 1 to 31 use in therapy that causes an immune response in a patient by administering it to a patient. The compound of claim 1, wherein: R 3 is alkyl and R 4 is alkyl. The compound of claim 1, wherein: R 3 and R 4 together with the carbon atom to which they are attached form cycloalkylene. The compound of claim 1, wherein: RJ and R &quot; together with the carbon atom to which they are attached forms a piperidine-4-long group substituted at the oxygen atom with ethyl, 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-long, tetrahydrothiopyran-4-yl or 1, 1-dioxotetrahydrothiopyran-4-yl. The compound of claim 1, wherein: R 6 is haloalkyl and R 7 and R 5 are hydrogen. The compound of claim 1, wherein: r * 7 R R is haloalkyl, R is haloalkyl, and R is hydrogen. The compound of claim 1, wherein: R 6 is haloalkyl, R 7 is alkyl, and R 8 is hydrogen. The compound of claim 1, wherein: R 1 is hydrogen, R 2 is cyclopropyl, R 3 is hydrogen, R 4 is ethyl, R 5 is 2-methylsulfonyl, R 6 is trifluoromethyl, R 7 is hydrogen, and R 8 is 4-fluoro-dichloro, namely, N-cyclopropyl-3- {4-methanesulfonyl-2- [2,2,2-trifluoro-1- (4-fluoro-femyl) -ethylamino] -butyrylamino} -2-oxo-pentanamide. The compound of claim 42, which is 7-cyclopropyl-3R- {4-methanesulfonyl-26 '- [2,2,2-trifluoro-1R- (4-fluoro-phenyl) -ethylamino] -butyramine} -2 oxo-pentanamide. r. The compound of claim 1, wherein: R 1 is hydrogen, R 2 is cyclopropyl, R 3 is hydrogen, R 4 is ethyl, R 5 is 2-phenylsulfonylmethyl, R 6 is trifluoroethyl, R 7 is hydrogen, and R 5 is 4-fluorophenyl, namely, 77-cyclopropyl-3- {3-benzenesulfonyl-2- [2,2,2-trifluoro-1- (4-fluoro-phenyl) -ethylamino] -propionylamino} -2-oxo-pentanamide. 45. The compound of claim 44 which is N-cyclopropyl-3S- {3-benzenesulfonyl-2R- [2,2,2-trifluoro-1 '- (4-fluoro-phenyl) -ethylamino] -propionylamino} - 2-oxo-pentanamide. The compound of claim 1, wherein: R 1 is hydrogen, R 2 is cyclopropyl, R 3 is hydrogen, R 4 is ethyl, R 5 is cyclopropylmethylsulfonylmethyl, R 6 is perfluoropropyl, R 7 is hydrogen, and R 8 is hydrogen, e.g. -cyclopropyl-3- [3-cyclopropylmethanesulfonyl-2- (2,2,3,3,4,4,4-heptafluoro-butylamino) -propiomlamino] -2-oxo-pentanamide. The compound of claim 46, which is 7 '-dldopropyl-3S' - [3-cyclopropylmethanesulfonyl-2-yl- (2,2,3,3,4,4,4-heptafluoro-butylamino) -propionylamino] - 2-oxo-pentanamtds.